Tricyclic delta-opioid modulators

ABSTRACT

The invention is directed to delta opioid receptor modulators. More specifically, the invention relates to tricyclic δ-opioid modulators. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using compounds of the invention are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Patent ApplicationNo. 60/599,131, filed Aug. 5, 2004, which is hereby incorporated byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

The term “opiate” has been used to designate pharmacologically activealkaloids derived from opium, e.g., morphine, codeine, and manysemi-synthetic congeners of morphine. After the isolation of peptidecompounds with morphine-like actions, the term opioid was introduced torefer generically to all drugs with morphine-like actions. Includedamong opioids are various peptides that exhibit morphine-like activity,such as endorphins, enkephalins and dynorphins. However, some sourcesuse the term “opiate” in a generic sense, and in such contexts, opiateand opioid are interchangeable. Additionally, the term opioid has beenused to refer to antagonists of morphine-like drugs as well as tocharacterize receptors or binding sites that combine with such agents.

Opioids are generally employed as analgesics, but they may have manyother pharmacological effects as well. Morphine and related opioidsproduce certain of their major effects on the central nervous anddigestive systems. The effects are diverse, including analgesia,drowsiness, mood changes, respiratory depression, dizziness, mentalclouding, dysphoria, pruritus, increased pressure in the biliary tract,decreased gastrointestinal motility, nausea, vomiting, and alterationsof the endocrine and autonomic nervous systems.

When therapeutic doses of morphine are given to patients with pain, theyreport that the pain is less intense, less discomforting, or entirelygone. In addition to experiencing relief of distress, some patientsexperience euphoria. However, when morphine in a selected pain-relievingdose is given to a pain-free individual, the experience is not alwayspleasant; nausea is common, and vomiting may also occur. Drowsiness,inability to concentrate, difficulty in mentation, apathy, lessenedphysical activity, reduced visual acuity, and lethargy may ensue.

Two distinct classes of opioid molecules can bind opioid receptors: theopioid peptides (e.g., the enkephalins, dynorphins, and endorphins) andthe alkaloid opiates (e.g., morphine, etorphine, diprenorphine andnaloxone). Subsequent to the initial demonstration of opiate bindingsites (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014), thedifferential pharmacological and physiological effects of both opioidpeptide analogues and alkaloid opiates served to delineate multipleopioid receptors. Accordingly, three molecularly and pharmacologicallydistinct opioid receptor types have been described: delta, kappa and mu.Furthermore, each type is believed to have sub-types (Wollemann, M., JNeurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature (1977)267:495-499).

All three of these opioid receptor types appear to share the samefunctional mechanisms at a cellular level. For example, the opioidreceptors cause inhibition of adenylate cyclase, and inhibition ofneurotransmitter release via both potassium channel activation andinhibition of Ca²⁺ channels (Evans, C. J., In: Biological Basis ofSubstance Abuse, S. G. Korenman & J. D. Barchas, eds., Oxford UniversityPress (1993); North, A. R., et al., Proc Natl Acad Sci USA (1990)87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990)87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975)72:3092-96). Although the functional mechanisms are the same, thebehavioral manifestations of receptor-selective drugs differ greatly(Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82).Such differences may be attributable in part to the anatomical locationof the different receptors.

Delta receptors have a more discrete distribution within the mammalianCNS than either mu or kappa receptors, with high concentrations in theamygdaloid complex, striatum, substantia nigra, olfactory bulb,olfactory tubercles, hippocampal formation, and the cerebral cortex(Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). The ratcerebellum is remarkably devoid of opioid receptors including deltaopioid receptors.

D. Delorme, E. Roberts and Z. Wei, World Patent WO/28275 (1998)discloses diaryl methylidenylpiperidines that are opioid analgesics, butdoes not disclose or suggest the compounds of the present invention.

C. Kaiser, and others (J. Med. Chem. 1974, Volume 17, pages 57-61)disclose some piperidylidene derivatives of thioxanthenes, xanthenes,dibenoxepins and acridans that are neuroleptic agents. These authors,however, do not disclose or suggest either the structure or the activityof the compounds of the present invention.

British Patent GB 1128734 (1966) discloses derivatives of6,11-dihydrodibenzo[b,e]oxepine that are anticholinergic,anti-convulsive, muscle-relaxing, sedating, diuretic, and/or vasoactiveagents. These, agents, however, differ significantly from the compoundsof the present invention both structurally and pharmacologically.

There is a continuing need for new delta opioid receptor modulators asanalgesics. There is a further need for delta opioid receptor selectiveagonists as analgesics having reduced side effects. There is also a needfor delta opioid receptor antagonists as immunosuppressants,antiinflammatory agents, agents for the treatment of neurological andpsychiatric conditions, agents for the treatment of urological andreproductive conditions, medicaments for drug and alcohol abuse, agentsfor treating gastritis and diarrhea, cardiovascular agents and agentsfor the treatment of respiratory diseases, having reduced side effects.

SUMMARY OF THE INVENTION

The present invention is directed to compositions comprising a compoundof Formula (I):

wherein:

-   -   G is —C(Z)NR₁R₂, C₆₋₁₀aryl, C₆₋₁₀arylthio, or a heterocycle        selected from the group consisting of imidazolyl, triazolyl,        tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,        imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,        pyrimidinyl, triazinyl, furyl, indazolyl, indolyl, indolinyl,        isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl,        quinolinyl, isoquinolinyl, and pyridinyl; wherein the C₆₋₁₀aryl        group in the C₆₋₁₀aryl-containing substituents of G, and the        heterocycles of G are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy,        hydroxy(C₁₋₈)alkanyl, carboxy(C₁₋₈)alkanyl,        C₁₋₈alkanylcarbonylamino, halogen, hydroxy, cyano, nitro, oxo,        thioxo, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl, C₁₋₈alkanylsulfonylamino,        aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,        aminothiocarbonylamino, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino;    -   R₁ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, and C₂₋₈alkynyl;    -   R₂ is a substituent selected from the group consisting of        hydrogen; C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkynyl; C₆₋₁₀aryl; and        C₃₋₈cycloalkanyl; provided that when Z is O or S, R₂ is other        than hydrogen or unsubstituted C₁₋₈alkanyl; and, wherein        C₁₋₈alkanyl of R₂ is optionally substituted with one to three        substituents independently selected from the group consisting of        phenyl, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanyloxy, C₁₋₆alkanylthio, hydroxy, fluoro, chloro, cyano,        aminocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, C₁₋₆alkanyloxycarbonyl, and        aryloxy; wherein the phenyl and aryloxy substituents of        C₁₋₈alkanyl are optionally further substituted with, and the        C₆₋₁₀aryl and C₃₋₈cycloalkanyl substituents of R₂ are optionally        substituted with, one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₁₋₈alkanyloxy, trifluoromethyl, trifluoromethoxy,        phenyl, halogen, cyano, hydroxy, C₁₋₈alkanylthio,        C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino;    -   or R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with phenyl (wherein phenyl is optionally        substituted with one to three C₁₋₄alkanyl or C₁₋₄alkanyloxy        substituents) and one to two additional substituents        independently selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   or, R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   R₃ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,        halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,        phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkenyl, phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl        and heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected        from the group consisting of benzo[1,3]dioxolyl, imidazolyl,        furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,        pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,        quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein        phenyl, naphthyl and heteroaryl are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        fluoro(C₁₋₆)alkanyl, thioureido, and fluoro(C₁₋₆)alkanyloxy;        alternatively, when phenyl and heteroaryl are optionally        substituted with alkanyl or alkanyloxy substituents attached to        adjacent carbon atoms, the two substituents can together form a        fused cyclic alkanyl or cycloheteroalkanyl selected from the        group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and        —O(CH₂)₁₋₃—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, aryl(C₂₋₆)alkynyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl, aminocarbonyl,        C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, mercapto, aminothiocarbonyl, amidino,        hydroxyamidino, phenylcarbonyl, —C(═NOH)phenyl, aminomethyl,        hydroxymethyl, methanesulfonylamino, C₆₋₁₀arylamino (wherein        C₆₋₁₀aryl is optionally substituted with one to three        substitutents independently selected from the group consisting        of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy),        dihydroimidazolyl, formylamino, thioformylamino, pyridinylamino,        cyano, hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl,        furanyl, imidazolyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl,        naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,        quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl,        fluoroalkanyl and fluoroalkanyloxy; or optionally, when R₄ is        two substituents attached to adjacent carbon atoms, the two        substituents together form a single fused moiety; wherein the        fused moiety is selected from the group consisting of        —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, —O(CH₂)₁₋₃O— and        —S—C(NH₂)═N—;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl and        fluoro(C₁₋₆)alkanyloxy;    -   A is absent or —(CH₂)_(m)—, wherein m is 2 or 3;    -   Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—;    -   X is O or S    -   n is 0 or 1;    -   Z is O, S, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or        N(phenyl); and enantiomers, diastereomers, tautomers, solvates,        or pharmaceutically acceptable salts thereof.

The present invention is also directed to compositions comprising acompound of Formula (Ib):

wherein:

-   -   G is bromo, chloro, cyano, trifluoromethanesulfonyloxy,        C₁₋₈alkanyloxycarbonyl, carboxy, —C(Z)NR₁R₂, C₆₋₁₀aryl,        C₆₋₁₀arylthio, or a heterocycle selected from the group        consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,        thiadiazolyl, oxathiadiazolyl, imidazolinyl,        tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl,        triazinyl, furyl, indazolyl, indolyl, indolinyl, isothiazolyl,        isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl, quinolinyl,        isoquinolinyl, and pyridinyl; wherein the C₆₋₁₀aryl group in the        C₆₋₁₀aryl-containing substituents of G and the heterocycles of G        are optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₈alkanyl,        C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl,        carboxy(C₁₋₈)alkanyl, C₁₋₈alkanylcarbonylamino, halogen,        hydroxy, cyano, nitro, oxo, thioxo, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl,        C₁₋₈alkanylsulfonylamino, aminocarbonyl, aminothiocarbonyl,        aminocarbonylamino, aminothiocarbonylamino,        C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl, and        C₁₋₆alkanyloxycarbonylamino;    -   R₁ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, and C₂₋₈alkynyl;    -   R₂ is a substituent selected from the group consisting of        hydrogen; C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkynyl; C₆₋₁₀aryl; and        C₃₋₈cycloalkanyl; provided that when Z is O or S, R₂ is other        than hydrogen or unsubstituted C₁₋₈alkanyl; and, wherein        C₁₋₈alkanyl of R₂ is optionally substituted with one to three        substituents independently selected from the group consisting of        phenyl, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanyloxy, C₁₋₆alkanylthio, hydroxy, fluoro, chloro, cyano,        aminocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, C₁₋₆alkanyloxycarbonyl, and        aryloxy; wherein the phenyl and aryloxy substituents of        C₁₋₈alkanyl are optionally further substituted with, and the        C₆₋₁₀aryl and C₃₋₈cycloalkanyl substituents of R₂ are optionally        substituted with, one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₁₋₈alkanyloxy, trifluoromethyl, trifluoromethoxy,        phenyl, halogen, cyano, hydroxy, C₁₋₈alkanylthio,        C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino;    -   or R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with phenyl (wherein phenyl is optionally        substituted with one to three C₁₋₄alkanyl or C₁₋₄alkanyloxy        substituents) and one to two additional substituents        independently selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   or, R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   R₃ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,        halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,        phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl        (C₁₋₈)alkenyl, phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and        heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from        the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,        pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl,        isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,        pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,        isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl, naphthyl        and heteroaryl are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        fluoro(C₁₋₆)alkanyl, thioureido, and fluoro(C₁₋₆)alkanyloxy;        alternatively, when phenyl and heteroaryl are optionally        substituted with alkanyl or alkanyloxy substituents attached to        adjacent carbon atoms, the two substituents can together form a        fused cyclic alkanyl or cycloheteroalkanyl selected from the        group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, aryl(C₂₋₆)alkynyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl, aminocarbonyl,        C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, mercapto, aminothiocarbonyl, amidino,        hydroxyamidino, phenylcarbonyl, —C(═NOH)phenyl, aminomethyl,        hydroxymethyl, methanesulfonylamino, C₆₋₁₀arylamino (wherein        C₆₋₁₀aryl is optionally substituted with one to three        substitutents independently selected from the group consisting        of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy),        dihydroimidazolyl, formylamino, thioformylamino, pyridinylamino,        cyano, hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl,        furanyl, imidazolyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl,        naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,        quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl,        fluoroalkanyl and fluoroalkanyloxy; or optionally, when R₄ is        two substituents attached to adjacent carbon atoms, the two        substituents together form a single fused moiety; wherein the        fused moiety is selected from the group consisting of        —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, —O(CH₂)₁₋₃O— and        —S—C(NH₂)═N—;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl and        fluoro(C₁₋₆)alkanyloxy;    -   A is absent or —(CH₂)_(m)—, wherein m is 2 or 3;    -   Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—;    -   X is O or S    -   n is 0 or 1;    -   Z is O, S, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or        N(phenyl); and enantiomers, diastereomers, tautomers, solvates,        or pharmaceutically acceptable salts thereof.

Finally, the present invention is directed to veterinary andpharmaceutical compositions containing compounds of Formula (I) andFormula (Ib) wherein the compositions are used to treat mild to severepain in warm-blooded animals.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following underlined terms are intended to have thefollowing meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containingfrom a to b carbon atoms inclusive. For example, C₁₋₃ denotes a radicalcontaining 1, 2 or 3 carbon atoms

“Alkyl:” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁-C₆) alkyl, with (C₁-C₃) beingparticularly preferred.

“Alkanyl:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon radical derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane. Typical alkanylgroups include, but are not limited to, methanyl; ethanyl; propanylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, etc.; and the like. In preferred embodiments, thealkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) being particularlypreferred.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon doublebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkene. The radical may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon triplebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkyne. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl,etc.; and the like.

“Heteroalkyl” and “Heteroalkanyl” refer to alkyl or alkanyl radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkanyl radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimino(—NR′—NR′—), azino (═N—N═), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂—), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

“Parent Aromatic Ring System:” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more rings are aromaticand one or more rings are saturated or unsaturated, such as, forexample, indane, indene, phenalene, etc. Typical parent aromatic ringsystems include, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like

“Aryl:” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In preferredembodiments, the aryl group is (C₅₋₂₀) aryl, with (C₅₋₁₀) beingparticularly preferred. Particularly preferred aryl groups are phenyland naphthyl groups.

“Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl. group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups are phenylalkanyls.

“Alkanyloxy:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon alcohol radical derived by the removal of thehydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyloxy;ethanyloxy; propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—),propan-2-yloxy ((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butanyloxygroups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

“Parent Heteroaromatic Ring System:” refers to a parent aromatic ringsystem in which one carbon atom is replaced with a heteroatom.Heteratoms to replace the carbon atoms include N, O, and S. Specificallyincluded within the definition of “parent heteroaromatic ring systems”are fused ring systems in which one or more rings are aromatic and oneor more rings are saturated or unsaturated, such as, for example,arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typicalparent heteroaromatic ring systems include, but are not limited to,carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like.

“Heteroaryl:” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, radicals derived from carbazole, imidazole, indazole,indole, indoline, indolizine, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine,pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In preferred embodiments, the heteroaryl group is a 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.

“Cycloheteroalkyl:” refers to a saturated or unsaturated monocyclic orbicyclic alkyl radical in which one carbon atom is replaced with N, O orS. In certain specified embodiments the cycloheteroalkyl may contain upto four heteroatoms independently selected from N, O or S. Typicalcycloheteroalkyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.

“Cycloheteroalkanyl:” refers to a saturated monocyclic or bicyclicalkanyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkanyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkanyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkanyl is a 3-6 memberedcycloheteroalkanyl.

“Cycloheteroalkenyl:” refers to a saturated monocyclic or bicyclicalkenyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkenyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkenyl moieties include, but are not limited to, radicalsderived from imidazoline, pyrazoline, pyrroline, indoline, pyran, andthe like. In preferred embodiments, the cycloheteroalkanyl is a 3-6membered cycloheteroalkanyl.

“Substituted:” refers to a radical in which one or more hydrogen atomsare each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O⁻, ═O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁻, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, amino,C₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkyl” substituent refers to a groupof the formula

An embodiment of the present invention is directed to a compound ofFormula (I) and Formula (Ib) wherein the structure is numbered asdefined herein.

The present invention is directed to analgesic and anti-pyretic uses ofcompositions comprising a compound of Formula (I):

wherein:

-   -   G is —C(Z)NR₁R₂, C₆₋₁₀aryl, C₆₋₁₀arylthio, or a heterocycle        selected from the group consisting of imidazolyl, triazolyl,        tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,        imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,        pyrimidinyl, triazinyl, furyl, indazolyl, indolyl, indolinyl,        isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl,        quinolinyl, isoquinolinyl, and pyridinyl; wherein the C₆₋₁₀aryl        group in the C₆₋₁₀aryl-containing substituents of G and the        heterocycles of G are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy,        hydroxy(C₁₋₈)alkanyl, carboxy(C₁₋₈)alkanyl,        C₁₋₈alkanylcarbonylamino, halogen, hydroxy, cyano, nitro, oxo,        thioxo, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl, C₁₋₈alkanylsulfonylamino,        aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,        aminothiocarbonylamino, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino;    -   R₁ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, and C₂₋₈alkynyl;    -   R₂ is a substituent selected from the group consisting of        hydrogen; C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkynyl; C₆₋₁₀aryl; and        C₃₋₈cycloalkanyl; provided that when Z is O or S, R₂ is other        than hydrogen or unsubstituted C₁₋₈alkanyl; and, wherein        C₁₋₈alkanyl of R₂ is optionally substituted with one to three        substituents independently selected from the group consisting of        phenyl, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanyloxy, C₁₋₆alkanylthio, hydroxy, fluoro, chloro, cyano,        aminocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, C₁₋₆alkanyloxycarbonyl, and        aryloxy; wherein the phenyl and aryloxy substituents of        C₁₋₈alkanyl are optionally further substituted with, and the        C₆₋₁₀aryl and C₃₋₈cycloalkanyl substituents of R₂ are optionally        substituted with, one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₁₋₈alkanyloxy, trifluoromethyl, trifluoromethoxy,        phenyl, halogen, cyano, hydroxy, C₁₋₈alkanylthio,        C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino;    -   or R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with phenyl (wherein phenyl is optionally        substituted with one to three C₁₋₄alkanyl or C₁₋₄alkanyloxy        substituents) and one to two additional substituents        independently selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   or, R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   R₃ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,        halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,        phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkenyl, phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl        and heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected        from the group consisting of benzo[1,3]dioxolyl, imidazolyl,        furanyl, pyridinyl, thiophenyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,        pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,        quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein        phenyl, naphthyl and heteroaryl are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        fluoro(C₁₋₆)alkanyl, thioureido, and fluoro(C₁₋₆)alkanyloxy;        alternatively, when phenyl and heteroaryl are optionally        substituted with alkanyl or alkanloxy substituents attached to        adjacent carbon atoms, the two substituents can together form a        fused cyclic alkanyl or cycloheteroalkanyl selected from the        group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, aryl(C₂₋₆)alkynyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl, aminocarbonyl,        C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, mercapto, aminothiocarbonyl, amidino,        hydroxyamidino, phenylcarbonyl, —C(═NOH)phenyl, aminomethyl,        hydroxymethyl, methanesulfonylamino, C₆₋₁₀arylamino (wherein        C₆₋₁₀aryl is optionally substituted with one to three        substitutents independently selected from the group consisting        of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy),        dihydroimidazolyl, formylamino, thioformylamino, pyridinylamino,        cyano, hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl,        furanyl, imidazolyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl,        naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,        quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl,        fluoroalkanyl and fluoroalkanyloxy; or optionally, when R₄ is        two substituents attached to adjacent carbon atoms, the two        substituents together form a single fused moiety; wherein the        fused moiety is selected from the group consisting of        —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, —O(CH₂)₁₋₃O— and        —S—C(NH₂)═N—;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl and        fluoro(C₁₋₆)alkanyloxy;    -   A is absent or —(CH₂)_(m)—, wherein m is 2 or 3;    -   Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—;    -   X is O or S    -   n is 0 or 1;    -   Z is O, S, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or        N(phenyl); and enantiomers, diastereomers, tautomers, solvates,        or pharmaceutically acceptable salts thereof.

The present invention is also directed to analgesic and anti-pyreticuses of compositions comprising a compound of Formula (Ib):

wherein:

-   -   G is bromo, chloro, cyano, trifluoromethanesulfonyloxy,        C₁₋₈alkanyloxycarbonyl, carboxy, —C(Z)NR₁R₂, C₆₋₁₀aryl,        C₆₋₁₀arylthio, or a heterocycle selected from the group        consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,        thiadiazolyl, oxathiadiazolyl, imidazolinyl,        tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl,        triazinyl, furyl, indazolyl, indolyl, indolinyl, isothiazolyl,        isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl, quinolinyl,        isoquinolinyl, and pyridinyl; wherein the C₆₋₁₀aryl group in the        C₆₋₁₀aryl-containing substituents of G and the heterocycles of G        are optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₈alkanyl,        C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl,        carboxy(C₁₋₈)alkanyl, C₁₋₈alkanylcarbonylamino, halogen,        hydroxy, cyano, nitro, oxo, thioxo, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl,        C₁₋₈alkanylsulfonylamino, aminocarbonyl, aminothiocarbonyl,        aminocarbonylamino, aminothiocarbonylamino,        C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl, and        C₁₋₆alkanyloxycarbonylamino;    -   R₁ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, and C₂₋₈alkynyl;    -   R₂ is a substituent selected from the group consisting of        hydrogen; C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkynyl; C₆₋₁₀aryl; and        C₃₋₈cycloalkanyl; provided that when Z is O or S, R₂ is other        than hydrogen or unsubstituted C₁₋₈alkanyl; and, wherein        C₁₋₈alkanyl of R₂ is optionally substituted with one to three        substituents independently selected from the group consisting of        phenyl, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanyloxy, C₁₋₆alkanylthio, hydroxy, fluoro, chloro, cyano,        aminocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, C₁₋₆alkanyloxycarbonyl, and        aryloxy; wherein the phenyl and aryloxy substituents of        C₁₋₈alkanyl are optionally further substituted with, and the        C₆₋₁₀aryl and C₃₋₈cycloalkanyl substituents of R₂ are optionally        substituted with, one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₁₋₈alkanyloxy, trifluoromethyl, trifluoromethoxy,        phenyl, halogen, cyano, hydroxy, C₁₋₈alkanylthio,        C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino;    -   or R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with phenyl (wherein phenyl is optionally        substituted with one to three C₁₋₄alkanyl or C₁₋₄alkanyloxy        substituents) and one to two additional substituents        independently selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   or, R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₈alkanyl,        hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, and halogen;    -   R₃ is a substituent selected from the group consisting of        hydrogen, C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl,        C₂₋₈alkynyl, C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,        halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,        phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkenyl, phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl        and heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected        from the group consisting of benzo[1,3]dioxolyl, imidazolyl,        furanyl, pyridinyl, thiophenyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,        pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,        quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein        phenyl, naphthyl and heteroaryl are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        fluoro(C₁₋₆)alkanyl, thioureido, and fluoro(C₁₋₆)alkanyloxy;        alternatively, when phenyl and heteroaryl are optionally        substituted with alkanyl or alkanyloxy substituents attached to        adjacent carbon atoms, the two substituents can together form a        fused cyclic alkanyl or cycloheteroalkanyl selected from the        group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, aryl(C₂₋₆)alkynyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl, aminocarbonyl,        C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, mercapto, aminothiocarbonyl, amidino,        hydroxyamidino, phenylcarbonyl, —C(═NOH)phenyl, aminomethyl,        hydroxymethyl, methanesulfonylamino, C₆₋₁₀arylamino (wherein        C₆₋₁₀aryl is optionally substituted with one to three        substitutents independently selected from the group consisting        of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy),        dihydroimidazolyl, formylamino, thioformylamino, pyridinylamino,        cyano, hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl,        furanyl, imidazolyl, indazolyl, indolyl, indolinyl,        isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl,        naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,        quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl,        fluoroalkanyl and fluoroalkanyloxy; or optionally, when R₄ is        two substituents attached to adjacent carbon atoms, the two        substituents together form a single fused moiety; wherein the        fused moiety is selected from the group consisting of        —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, —O(CH₂)₁₋₃O— and        —S—C(NH₂)═N—;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl and        fluoro(C₁₋₆)alkanyloxy;    -   A is absent or —(CH₂)_(m)—, wherein m is 2 or 3;    -   Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—;    -   X is O or S    -   n is 0 or 1;    -   Z is O, S, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or        N(phenyl); and enantiomers, diastereomers, tautomers, solvates,        or pharmaceutically acceptable salts thereof.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably:

-   -   a) G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the        group consisting of imidazolyl, triazolyl, tetrazolyl,        oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl,        tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl,        triazinyl, furyl, isothiazolyl, isoxazolyl, oxazolyl,        isoxadiazolyl, quinolinyl, and pyridinyl; wherein phenyl and the        heterocycles of G are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₈alkanyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl,        carboxy(C₁₋₈)alkanyl, C₁₋₈alkanylcarbonylamino, halogen,        hydroxy, cyano, oxo, thioxo, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, aminocarbonyl,        aminothiocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino;    -   b) G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the        group consisting of imidazolyl, tetrazolyl, oxadiazolyl,        thiadiazolyl, oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl,        pyrimidinyl, triazinyl, furyl, isothiazolyl, isoxazolyl,        oxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; wherein        phenyl and the heterocycles of G are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy, hydroxy(C₁₋₄)alkanyl,        carboxy(C₁₋₄)alkanyl, C₁₋₄alkanylcarbonylamino, hydroxy, cyano,        oxo, thioxo, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₈alkanylthio, aminocarbonyl, aminothiocarbonyl,        C₁₋₈alkanylaminocarbonyl, and di(C₁₋₈alkanyl)aminocarbonyl;    -   c) G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the        group consisting of imidazolyl, tetrazolyl, oxadiazolyl,        thiadiazolyl, oxathiadiazolyl, thienyl, isothiazolyl,        isoxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; wherein        phenyl and the heterocycles of G are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy, hydroxy(C₁₋₄)alkanyl,        C₁₋₄alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, and        aminocarbonyl;    -   d) R₁ is a substituent selected from the group consisting of        hydrogen and C₁₋₄alkanyl;    -   e) R₁ is selected from the group consisting of hydrogen, methyl,        ethyl, and propyl;    -   f) R₁ is selected from the group consisting of hydrogen, methyl,        or ethyl;    -   g) R₂ is selected from the group consisting of hydrogen;        C₁₋₄alkanyl; phenyl; and C₃₋₆cycloalkanyl; provided that when Z        is O or S, R₂ is other than hydrogen or unsubstituted        C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is optionally substituted        with one to three substituents independently selected from the        group consisting of phenyl, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, C₁₋₄alkanyloxy, hydroxy, fluoro, chloro,        cyano, aminocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, and phenoxy; wherein the phenyl        and phenoxy substituents of C₁₋₄alkanyl are optionally further        substituted with, and the phenyl and C₃₋₆cycloalkanyl        substituents of R₂ are optionally substituted with, one to three        substituents independently selected from the group consisting of        C₁₋₈alkanyl, C₁₋₈alkanyloxy, trifluoromethyl, phenyl, fluoro,        hydroxy, C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl, and        C₁₋₈alkanylsulfonylamino; or R₁ and R₂ taken together with the        nitrogen to which they are attached form a 5-7 membered        cycloheteroalkyl optionally substituted with phenyl (wherein        phenyl is optionally substituted with C₁₋₄alkanyloxy or        hydroxy), C₁₋₄alkanyl, or hydroxy;    -   h) R₂ is selected from the group consisting of C₁₋₄alkanyl,        phenyl, and C₃₋₆cycloalkanyl; provided that when Z is O or S, R₂        is other than unsubstituted C₁₋₄alkanyl; and, wherein        C₁₋₄alkanyl is optionally substituted with one to three        substituents independently selected from the group consisting of        phenyl, C₁₋₄alkanyloxy, hydroxy, fluoro, aminocarbonyl,        C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl, and        phenoxy; wherein the phenyl and phenoxy substituents of        C₁₋₄alkanyl are optionally further substituted with, and the        phenyl of R₂ is optionally substituted with, one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, hydroxy, and        C₁₋₆alkanylthio; or R₁ and R₂ taken together with the nitrogen        to which they are attached form a pyrrolidinyl or piperidinyl        ring wherein said pyrrolidinyl or piperidinyl is optionally        substituted with a substituent selected from the group        consisting of C₁₋₄alkanyl and hydroxy;    -   i) R₂ is selected from the group consisting of C₁₋₄alkanyl and        phenyl; provided that when Z is O or S, R₂ is other than        unsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is        optionally substituted with one to three substituents        independently selected from the group consisting of phenyl,        C₁₋₄alkanyloxy, hydroxy, fluoro, and phenoxy; wherein the phenyl        and phenoxy substituents of C₁₋₄alkanyl are optionally further        substituted with, and the phenyl of R₂ is optionally substituted        with, one to three substituents independently selected from the        group consisting of C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, and        hydroxy; or R₁ and R₂taken together with the nitrogen to which        they are attached form a pyrrolidinyl or piperidinyl ring        wherein said pyrrolidinyl or piperidinyl is optionally        substituted with a substituent selected from the group        consisting of C₁₋₃alkanyl and hydroxy;    -   j) R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein        heteroaryl is selected from the group consisting of        benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,        indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,        tetrazolyl; wherein phenyl and heteroaryl are optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₆alkanyloxy and        hydroxy; or optionally, when phenyl and heteroaryl are        optionally substituted with two substituents attached to        adjacent carbon atoms, the two substituents together form a        single fused moiety; wherein the moiety is selected from        —O(CH₂)₁₋₃O—;    -   k) R₃ is selected from the group consisting of hydrogen, methyl,        allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,        methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and        heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from        the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,        pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,        isoquinolinyl, tetrazolyl; wherein the phenyl in any        phenyl-containing substituent is optionally substituted with one        hydroxyl group;    -   l) R₃ is hydrogen, methyl, allyl, or heteroarylmethyl wherein        heteroaryl is selected from the group consisting of        benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl;    -   m) R₄ is one to three substituents independently selected from        the group consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,        aminocarbonyl, aminothiocarbonyl, hydroxyamidino, formylamino,        C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen,        hydroxy, C₆₋₁₀aryl; chromanyl, chromenyl, furanyl, imidazolyl,        indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,        isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,        pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,        quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,        tetrazolyl, thiazolyl, and thienyl;    -   n) R₄ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,        halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl,        indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl,        thiazolyl, thienyl, hydroxy, and aminocarbonyl;    -   o) R₄ is one to two substituents independently selected from the        group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5-        or 6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy;    -   p) R₅ is one to two substituents independently selected from the        group consisting of hydrogen and halogen;    -   q) R₅ is hydrogen;    -   r) A is absent or —(CH₂)₂—;    -   s) A is —(CH₂)₂—;    -   t) X is O or S;    -   u) n is 0;    -   v) Z is O, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or        N(phenyl);    -   w) Z is O, NH, or N(OH);    -   x) Z is O or NH;        and combinations of a) through x) above.

One embodiment of the present invention is a compound of Formula (I)wherein:

-   -   G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the        group consisting of imidazolyl, triazolyl, tetrazolyl,        oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl,        tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl,        triazinyl, furyl, isothiazolyl, isoxazolyl, oxazolyl,        isoxadiazolyl, quinolinyl, and pyridinyl; wherein phenyl and the        heterocycles of G are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₈alkanyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl,        carboxy(C₁₋₈)alkanyl, C₁₋₈alkanylcarbonylamino, halogen,        hydroxy, cyano, oxo, thioxo, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, aminocarbonyl,        aminothiocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino;    -   R₁ is hydrogen or C₁₋₄alkanyl;    -   R₂ is selected from the group consisting of hydrogen;        C₁₋₄alkanyl; phenyl; and C₃₋₆cycloalkanyl; provided that when Z        is O or S, R₂ is other than hydrogen or unsubstituted        C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is optionally substituted        with one to three substituents independently selected from the        group consisting of phenyl, amino, C₁₋₆alkanylamino,        di(C₁₋₆alkanyl)amino, C₁₋₄alkanyloxy, hydroxy, fluoro, chloro,        cyano, aminocarbonyl, C₁₋₈alkanylaminocarbonyl,        di(C₁₋₈alkanyl)aminocarbonyl, and phenoxy; wherein the phenyl        and phenoxy substituents of C₁₋₄alkanyl are optionally further        substituted with, and the phenyl and C₃₋₆cycloalkanyl        substituents of R₂ are optionally substituted with, one to three        substituents independently selected from the group consisting of        C₁₋₈alkanyl, C₁₋₈alkanyloxy, trifluoromethyl, phenyl, fluoro,        hydroxy, C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl, and        C₁₋₈alkanylsulfonylamino;    -   or R₁ and R₂ taken together with the nitrogen to which they are        attached form a 5-7 membered cycloheteroalkyl optionally        substituted with phenyl (wherein phenyl is optionally        substituted with C₁₋₄alkanyloxy or hydroxy), C₁₋₄alkanyl, or        hydroxy;    -   R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein        heteroaryl is selected from the group consisting of        benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,        indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,        tetrazolyl; wherein phenyl and heteroaryl are optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₆alkanyloxy and        hydroxy; or optionally, when phenyl and heteroaryl are        optionally substituted with two substituents attached to        adjacent carbon atoms, the two substituents together form a        single fused moiety; wherein the moiety is selected from        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,        aminocarbonyl, aminothiocarbonyl, hydroxyamidino, formylamino,        C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen,        hydroxy, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl,        indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,        isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,        pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,        quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,        tetrazolyl, thiazolyl, and thienyl;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen and halogen;    -   A is absent or CH₂CH₂;    -   Y is O, S, CH₂O or OCH₂;    -   Z is O, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or        N(phenyl); and    -   enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   -   G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the        group consisting of imidazolyl, tetrazolyl, oxadiazolyl,        thiadiazolyl, oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl,        pyrimidinyl, triazinyl, furyl, isothiazolyl, isoxazolyl,        oxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; wherein        phenyl and the heterocycles of G are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy, hydroxy(C₁₋₄)alkanyl,        carboxy(C₁₋₄)alkanyl, C₁₋₄alkanylcarbonylamino, hydroxy, cyano,        oxo, thioxo, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₈alkanylthio, aminocarbonyl, aminothiocarbonyl,        C₁₋₈alkanylaminocarbonyl, and di(C₁₋₈alkanyl)aminocarbonyl;    -   R₁ is selected from the group consisting of hydrogen, methyl,        ethyl, and propyl;    -   R₂ is selected from the group consisting of C₁₋₄alkanyl, phenyl,        and C₃₋₆cycloalkanyl; provided that when Z is O or S, R₂ is        other than unsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl        is optionally substituted with one to three substituents        independently selected from the group consisting of phenyl,        C₁₋₄alkanyloxy, hydroxy, fluoro, aminocarbonyl,        C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl, and        phenoxy; wherein the phenyl and phenoxy substituents of        C₁₋₄alkanyl are optionally further substituted with, and the        phenyl of R₂ is optionally substituted with, one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, hydroxy, and        C₁₋₆alkanylthio; or R₁ and R₂ taken together with the nitrogen        to which they are attached form pyrrolidinyl or piperidinyl ring        wherein said pyrrolidinyl or piperidinyl is optionally        substituted with a substituent selected from the group        consisting of C₁₋₃alkanyl and hydroxy;    -   R₃ is selected from the group consisting of hydrogen, methyl,        allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,        methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and        heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from        the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,        pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,        isoquinolinyl, tetrazolyl wherein the phenyl in any        phenyl-containing substituent is optionally substituted with one        hydroxyl group;    -   R₄ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,        halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl,        indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl,        thiazolyl, thienyl, hydroxy, and aminocarbonyl;    -   R₅ is hydrogen;    -   A is CH₂CH₂;    -   Y is O or S;    -   Z is O, NH, or N(OH); and    -   enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein:

-   -   G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the        group consisting of imidazolyl, tetrazolyl, oxadiazolyl,        thiadiazolyl, oxathiadiazolyl, thienyl, isothiazolyl,        isoxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; wherein        phenyl and the heterocycles of G are optionally substituted with        one to three substituents independently selected from the group        consisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy, hydroxy(C₁₋₄)alkanyl,        C₁₋₄alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, and        aminocarbonyl;    -   R₁ is hydrogen, methyl, or ethyl;    -   R₂ is selected from the group consisting of C₁₋₄alkanyl, phenyl,        and C₃₋₆cycloalkanyl; provided that when Z is O or S, R₂ is        other than unsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl        is optionally substituted with one to three substituents        independently selected from the group consisting of phenyl,        C₁₋₄alkanyloxy, hydroxy, fluoro, aminocarbonyl,        C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl, and        phenoxy; wherein the phenyl and phenoxy substituents of        C₁₋₄alkanyl are optionally further substituted with, and the        phenyl of R₂ is optionally substituted with, one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, hydroxy, and        C₁₋₆alkanylthio; or R₁ and R₂taken together with the nitrogen to        which they are attached form pyrrolidinyl or piperidinyl ring        wherein said pyrrolidinyl or piperidinyl is optionally        substituted with a substituent selected from the group        consisting of C₁₋₃alkanyl and hydroxy;    -   R₃ is hydrogen, methyl, allyl, or heteroarylmethyl wherein        heteroaryl is selected from the group consisting of        benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl;    -   R₄ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,        halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl,        indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl,        thiazolyl, thienyl, hydroxy, and aminocarbonyl;    -   A is CH₂CH₂;    -   Y is O or S;    -   Z is O or NH; and    -   enantiomers, diasteromers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   -   G is selected from —C(Z)NR₁R₂, 2-methylcarbonylaminophenyl,        2-aminocarbonyl-phenyl, 1H-tetrazol-5-yl,        2-methyl-tetrazol-5-yl, 4H-[1,2,4]-oxadiazol-5-oxo-3-yl,        4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,        4H-[1,2,4]thiadiazol-5-oxo-3-yl,        [1,2,3,5]oxathiadiazol-2-oxo-4-yl, or pyridin-3-yl;    -   R₁ is hydrogen, methyl, or ethyl;    -   R₂ is selected from the group consisting of C₁₋₄alkanyl and        phenyl; provided that when Z is O or S, R₂ is other than        unsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is        optionally substituted with one to three substituents        independently selected from the group consisting of phenyl,        C₁₋₄alkanyloxy, hydroxy, fluoro, and phenoxy; wherein the phenyl        and phenoxy substituents of C₁₋₄alkanyl are optionally further        substituted with, and the phenyl of R₂ is optionally substituted        with, one to three substituents independently selected from the        group consisting of C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, and        hydroxy;    -   or R₁ and R₂ taken together with the nitrogen to which they are        attached form a pyrrolidinyl or piperidinyl ring;    -   R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein        heteroaryl is selected from the group consisting of hydrogen,        methyl, allyl, or heteroarylmethyl; wherein heteroaryl is        selected from the group consisting of benzo[1,3]dioxolyl,        imidazolyl, furanyl, pyridinyl, and thienyl; wherein phenyl and        heteroaryl are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyloxy and hydroxy; or optionally, when phenyl and        heteroaryl are optionally substituted with two substituents        attached to adjacent carbon atoms, the two substituents together        form a single fused moiety; wherein the moiety is selected from        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,        halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl,        indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl,        thiazolyl, thienyl, hydroxy, and aminocarbonyl;    -   R₅ is hydrogen;    -   A is CH₂CH₂;    -   Y is O or S;    -   Z is O or NH; and        enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein G is independently selectedfrom —C(Z)NR₁R₂, 2-methylcarbonylaminophenyl, 2-aminocarbonyl-phenyl,1H-tetrazol-5-yl, 2-methyl-tetrazol-5-yl,4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, andpyridin-3-yl; R₁ is hydrogen, methyl, or ethyl; R₂ is a substituentselected from the group consisting of C₁₋₄alkanyl and phenyl; providedthat when Z is O or S, R₂ is other than unsubstituted C₁₋₄alkanyl; and,wherein C₁₋₄alkanyl is optionally substituted with one to threesubstituents independently selected from the group consisting of phenyl,C₁₋₄alkanyloxy, hydroxy, and 2,6-dimethyl-phenoxy; wherein phenyl of R₂is optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₃alkanyl, C₁₋₃alkanyloxy, orhydroxy; or R₁ and R₂ taken together with the nitrogen to which they areattached form a pyrrolidinyl or piperidinyl ring wherein saidpyrrolidinyl or piperidinyl is optionally substituted with a substituentselected from the group consisting of C₁₋₃alkanyl and hydroxy; R₃ is asubstituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl,allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, and thiophen-2-ylmethyl; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thienyl, hydroxy, and aminocarbonyl; A is CH₂CH₂; Y is O or S; and Z isO or NH.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein G is selected from—C(Z)NR₁R₂, 2-methylcarbonylaminophenyl, 2-aminocarbonyl-phenyl,1H-tetrazol-5-yl, 2-methyl-tetrazol-5-yl,4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, orpyridin-3-yl; R₁ is hydrogen, methyl, or ethyl; R₂ is a substituentselected from the group consisting of C₁₋₄alkanyl and phenyl; providedthat when Z is O or S, R₂ is other than unsubstituted C₁₋₄alkanyl; and,wherein C₁₋₄alkanyl is optionally substituted with one to threesubstituents independently selected from the group consisting of phenyl,C₁₋₄alkanyloxy, hydroxy, and 2,6-dimethyl-phenoxy; and wherein phenyl ofR₂ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₃alkanyl,C₁₋₃alkanyloxy, fluoro, or hydroxy; or R₁ and R₂ taken together with thenitrogen to which they are attached form a pyrrolidinyl or piperidinylring wherein said pyrrolidinyl or piperidinyl is optionally substitutedwith a substituent selected from the group consisting of C₁₋₃alkanyl andhydroxy; R₃ is a substituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl methyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxyethyl, methoxyethyl, allyl, furan-3-yl methyl, H, Me,methylthioethyl, and phenethyl; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy; A is CH₂CH₂; Y is O or S; and Z is O or NH.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein G is selected from—C(Z)NR₁R₂, 2-methylcarbonylaminophenyl, 2-aminocarbonyl-phenyl,1H-tetrazol-5-yl, 2-methyl-tetrazol-5-yl,4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, orpyridin-3-yl; R₁ is hydrogen, methyl, or ethyl; R₂ is a substituentselected from the group consisting of C₁₋₄alkanyl and phenyl; providedthat when Z is O or S, R₂ is other than unsubstituted C₁₋₄alkanyl; and,wherein C₁₋₄alkanyl is optionally substituted with one to threesubstituents independently selected from the group consisting of phenyl,C₁₋₄alkanyloxy, hydroxy, and 2,6-dimethyl-phenoxy; wherein phenyl of R₂is optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₃alkanyl, C₁₋₃alkanyloxy,fluoro, or hydroxy; or R₁ and R₂taken together with the nitrogen towhich they are attached form a pyrrolidinyl or piperidinyl ring whereinsaid pyrrolidinyl or piperidinyl is optionally substituted with asubstituent selected from the group consisting of C₁₋₃alkanyl andhydroxy; R₃ is a substituent selected from the group consisting of H,benzo[1,3]dioxol-5-ylmethyl, 1-H-imidazol-4-yl methyl, furan-3-ylmethyl,pyridin-2-ylmethyl, and phenyliminomethyl; R₄ is a substituentindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy; A is CH₂CH₂; Y is O or S; and Z is O or NH.

Another embodiment of the present invention is directed to a compound ofFormula (I) wherein R₄ is preferably substituted at the 5- or 6-positionof Formula (I).

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    [1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    N-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is N-(1    (S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;    R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-phenylethyl-aminocarbonyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is    N-cyclohexyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and    Y is O;-   a compound of Formula (I) wherein G is 3-hydroxymethyl-phenyl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is N-hydroxyamidino; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   compound of Formula (I) wherein G is 2-aminophenyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 5-ethyl-1H-imidazol-2-yl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(1(R)-hydroxymethyl-2-phenyl-eth-1-yl)-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is N, N-diisobutylamidino; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 4-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(1S-methoxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methoxypyridin-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 4,5-dihydro-1H-imidazol-2-yl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(4-phenyl)-cyclohexyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    3-methyl-4H-[1,2,4]triazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    5-methyl-[1,2,4]oxadiazol-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-(1(S)-hydroxymethyl-1-methoxycarbonyl)aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 3-hydroxy-phenyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is isopropylamidino; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is phenylmethylaminocarbonyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    1,4,5,6-tetrahydropyrimidin-2-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is 4-aminophenyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    C-piperidin-1-yl-methyleneamine; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is 2-methoxyphenyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is cyclopentylaminocarbonyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 3-methylphenyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is phenylaminocarbonyl; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N,N-bis(2,2,2-trifluoro-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H; R₅    is H; and Y is O;-   a compound of Formula (I) wherein G is isobutylamidino; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    C-morpholin-4-yl-methyleneamine; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is 3-fluorophenyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-benzyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is 4-methanesulfonyl-phenyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 4-fluorophenyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is thiophen-3-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 3-methoxyphenyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is phenylmethylaminocarbonyl; R₃    is ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is phenylaminocarbonyl; R₃ is    ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is cyclopentylaminocarbonyl; R₃    is ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ is    ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-[(4-trifluoromethyl)-cyclohexyl]-aminocarbonyl; R₃ is H; R₄ is H;    R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    3-methanesulfonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-2,2,2,-trifluoroethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    3-[(3-methoxy)phenyl]piperidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    N-4-fluorophenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    N-(1(R)-hydroxymethyl-3-methyl-but-1-yl)-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    (3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    (3(S)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-ethyl)-N-methyl-aminocarbonyl; R₃ is ethoxycarbonyl; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is phenylthio; R₃ is H; R₄ is H;    R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is 5-hydroxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄is H; R₅is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (Ib) wherein G is methoxycarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-1,1-dimethylethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅    is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is fur-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is thien-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is    5-methoxy; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is    5-hydroxy; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is 1-methyl-pyrazol-3-yl; R₃ is    H; R₄ is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is methyl;    R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    fur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is methyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is 1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is fur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is t-butoxycarbonyl; R₄ is H;    R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-hydroxyethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    N-(2-hydroxyethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    (3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    trifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    trifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is trifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is trifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is    H; and Y is O; and-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H;    and Y is O.

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    [1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄is H; R₅is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is    N-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is N-(1    (S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;    R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-phenylethyl-aminocarbonyl;    R₃ is H; R₄is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-cyclohexyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and    Y is O;-   a compound of Formula (I) wherein G is 3-hydroxymethyl-phenyl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is N-hydroxyamidino; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-aminophenyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 5-ethyl-1H-imidazol-2-yl; R₃    is H; R₄ is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(1(R)-hydroxymethyl-2-phenyl-eth-1-yl)-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is N, N-diisobutylamidino; R₃ is    H; R₄ is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 4-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(1S-methoxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methoxypyridin-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 4,5-dihydro-1H-imidazol-2-yl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(4-phenyl)-cyclohexyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    3-methyl-4H-[1,2,4]triazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ is    ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    3-methanesulfonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-2,2,2,-trifluoroethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    3-[(3-methoxy)phenyl]piperidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    N-4-fluorophenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    N-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    (3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    (3(S)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-1,1-dimethyl-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅    is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is fur-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is thien-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is    5-hydroxy; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is 1-methyl-pyrazol-3-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is methyl;    R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    fur-3-ylmethyl; R₄ is H; R₅is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    pyridin-2-ylmethyl;R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is 1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is fur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is    N-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    (3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is    H; and Y is O; and-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H;    and Y is O.

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    [1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    N-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-(1(S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl; R₃ is    H; R₄ is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is 2-phenylethyl-aminocarbonyl;    R₃ is H; R₄is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-cyclohexyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and    Y is O;-   a compound of Formula (I) wherein G is 3-hydroxymethyl-phenyl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is N-hydroxyamidino; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-aminophenyl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 5-ethyl-1H-imidazol-2-yl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(1(R)-hydroxymethyl-2-phenyl-eth-1-yl)-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ is    ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-2,2,2,-trifluoroethyl-aminocarbonyl; R₃is H; R₄is H; R₅is H; and Y    is O;-   a compound of Formula (I) wherein G is    3-[(3-methoxy)phenyl]piperidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    N-4-fluorophenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    N-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    (3(S)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄is H; R₅is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is fur-3-yl; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is    5-hydroxy; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    fur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is    pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is fur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is diethylamidino; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is    H; and Y is O; and-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H;    and Y is O.

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylaminophenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃    is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is    H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    [1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    N-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄ is    H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    N-(1(S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methyl-tetrazol-5-yl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl; R₃ is    H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-phenylethyl-aminocarbonyl;    R₃ is H; R₄is H; R₅is H; and Y is O;-   a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl;    R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ is    ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    N-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is    pyridin-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is 5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is    O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y    is O;-   a compound of Formula (I) wherein G is 4H-[1    ,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    Is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄    is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is H; R₄ is 5-methoxy;R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is    5-hydroxy; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;    R₃ is pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;    R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;    and Y is O;-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is    H; and Y is O; and-   a compound of Formula (I) wherein G is    4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H;    and Y is O.

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   a compound of Formula (1b) wherein G is carboxy; R₃ is H; R₄ is H;    R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is methoxycarbonyl; R₃ is H; R₄    is H; R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is methoxycarbonyl; R₃ is    ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O;    -   a compound of Formula (1b) wherein G is methoxycarbonyl; R₃ is        H; R₄ is H; R₅ is H; and Y is S;-   a compound of Formula (1b) wherein G is cyano; R₃ is H; R₄ is H; R₅    is H; and Y is O;-   a compound of Formula (Ib) wherein G is methoxycarbonyl; R₃ is H; R₄    is 6-methoxycarbonyl; R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is bromo; R₃ is H; R₄ is    5-methoxy; R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is bromo; R₃ is H; R₄ is H; R₅    is H; and Y is S;-   a compound of Formula (1b) wherein G is cyano; R₃ is H; R₄ is H; R₅    is H; and Y is S;-   a compound of Formula (1b) wherein G is cyano; R₃ is H; R₄ is H; R₅    is H; and Y is O;-   a compound of Formula (1b) wherein G is cyano;R₃ is H; R₄ is H; R₅    is H; and Y is O;-   a compound of Formula (1b) wherein G is cyano; R₃ is    trifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is cyano; R₃ is    trifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is carboxy; R₃ is    t-butoxycarbonyl; R₄ is H; R₅ is H; and Y is O;-   a compound of Formula (1b) wherein G is carboxy; R₃ is H; R₄ is H;    R₅ is H; and Y is O; and-   a compound of Formula (1b) wherein G is carboxy; R₃ is H; R₄ is H;    R₅ is H; and Y is O.

Another embodiment of the present invention is a composition comprisingthe dextrorotatory enantiomer of a compound of formula (I), wherein saidcomposition is substantially free from the levorotatory isomer of saidcompound. In the present context, substantially free means less than25%, preferably less than 10%, more preferably less than 5%, even morepreferably less than 2% and even more preferably less than 1% of thelevorotatory isomer calculated as.${\%\quad{levorotatory}} = {\frac{\left( {{mass}\quad{levorotatory}} \right)}{\left( {{mass}\quad{dextrorotatory}} \right) + \left( {{mass}\quad{levorotatory}} \right)} \times 100}$

Another embodiment of the present invention is a composition comprisingthe levorotatory enantiomer of a compound of formula (I) wherein saidcomposition is substantially free from the dextrorotatory isomer of saidcompound. In the present context, substantially free from means lessthan 25 %, preferably less than 10%, more preferably less than 5%, evenmore preferably less than 2% and even more preferably less than 1% ofthe dextrorotatory isomer calculated as${\%\quad{dextrorotatory}} = {\frac{\left( {{mass}\quad{dextrorotatory}} \right)}{\left( {{mass}\quad{dextrorotatory}} \right) + \left( {{mass}\quad{levorotatory}} \right)} \times 100}$

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33,201-217; J.Pharm. Sci., 1997 (Jan), 66, 1, 1). Other salts well known to those inthe art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically, acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilizers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as analgesics is required for a subject in need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

The compounds of the present invention may be used to treat mild tosevere pain in warm-blooded animals such as humans by administration ofan analgesically effective dose. The dosage range would be from about0.1 mg to about 15,000 mg, in particular from about 50 mg to about 3500mg or, more particularly from about 100 mg to about 1000 mg of activeingredient in a regimen of about 1 to 4 times per day for an average (70kg) human; although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the types of pain being treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing 0.01, 10.0, 50.0, 100, 150,200, 250, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated.

Examples of pain intended to be within the scope of the presentinvention include, but are not limited to, inflammatory pain, centrallymediated pain, peripherally mediated pain, visceral pain, structural orsoft tissue injury related pain, progressive disease related pain,neuropathic pain and acute pain such as caused by acute injury, traumaor surgery and chronic pain such as headache and that caused byneuropathic conditions, post-stroke conditions, cancer, and migraine.

Compounds of the present invention are also useful asimmunosuppressants, antiinflammatory agents, agents for the treatmentand prevention of neurological and psychiatric conditions, for instance,depression and Parkinson's disease, agents for the treatment ofurological and reproductive conditions, for instance, urinaryincontinence and premature ejaculation, medicaments for drug and alcoholabuse, agents for treating gastritis and diarrhea, cardiovascular agentsand cardioprotective agents and agents for the treatment of respiratorydiseases.

The compounds of the present invention are also useful in treating paincaused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine,headache, toothache, burn, sunburn, snake bite (in particular, venomoussnake bite), spider bite, insect sting, neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminalneuralgia, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory boweldisease, irritable bowel syndrome, sinus headache, tension headache,labor, childbirth, menstrual cramps, and cancer.

In regard to the use of the present compounds in treatment of thedisases or conditions such as those listed above, a therapeuticallyeffective dose can be determined by persons skilled in the art by theuse of established animal models. Such a dose would likely fall in therange of from about 0.01 mg to about 15,000 mg of active ingredientadministered 1 to 4 times per day for an average (70 kg) human.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follow. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

The preparation of compounds of this invention is illustrated in Schemes1 and 2. Both schemes proceed with the same overall strategy. In stage1, an intermediate 1 is prepared with two benzene rings connected by alinker —Y—. The linker —Y— should be of the form —(CH₂)_(n)—X— where Xmay be oxygen or sulfur and n may be zero or one. One benzene ring bearsa group, Q, which is a group readily transformable to a substituent G asdefined herein. Examples of such Q groups are fluoro, bromo, cyano,iodo, carboxy, or trifluoromethanesulfonyloxy. In some instances, the 0substituents may be the same as the G substituents of Formula (Ib). Onebenzene ring must bear a carboxylic acid, or a precursor to a carboxylicacid, positioned ortho to the linker —Y—. The atom X may be attachedeither to the benzene ring bearing the Q group or the benzene ringlacking the Q group. Schemes 1 and 2 differ in that in scheme 1, thecarboxylic acid is on the benzene ring bearing the Q group (1A and 1B)while in scheme 2 the carboxylic acid function is on the benzene ringwhich does not bear the group Q (1C, 1D and 1E).

In stage 1 the linker —Y-— is constructed between two monocyclicintermediates. For Scheme 1, Stage 1, the bridge may be constructed bynucleophilic aromatic displacement of fluoride from intermediate int 2(where Q′ is an electron withdrawing group, readily convertible to acarboxylic acid, for instance cyano or carbalkoxy) by a phenoxide,thiophenoxide, benzyloxide or benzylthiooxide, int 1. The 1A compoundsare then obtained by hydrolysis with an alkali metal hydroxide. Forconstruction of the bridge of compounds of type 1B, a benzyl halideintermediate compound (int 5) is prepared by NBS bromination of thecorresponding toluene (int 4). Reaction of int 5 with a phenoxide orphenylthiooxide leads to int 6. The 1B compound may be obtained byalkali metal hydroxide hydrolysis of int 6.

For Scheme 2, Stage 1, in order to prepare 1C compounds, a phthalide(int 7) may be caused to react with a phenoxide or phenylthiooxide (int8). For preparation of compounds of formula 1D, the bridge may beconstructed by nucleophilic aromatic displacement of fluoride fromintermediate int 9 by phenoxides or phenylthiooxides (int 8). Thecompounds of formula 1D are then obtained by hydrolysis of int 10 withan alkali metal hydroxide. For construction of the Y-linker of compoundsof intermediate 13, benzyl bromide compounds of int 12 may be reactedwith a phenoxide or phenylthiooxide (int 11). The compounds of formula1E may then be obtained by hydrolysis of int 13 with an alkali metalhydroxide.

Following Stage 1, the schemes merge. In Stage 2, compounds of formula 1are converted by cycloacylation to ketones of formula 2, using, forinstance, BF₃Et₂O-trifluoroacetic acid or polyphosphoric acid.Alternatively, the cyclization may be effected by converting an acid offormula 1 to an acid chloride using a chlorinating agent such as thionylchloride or the like, followed by Friedel-Crafts ring closure in thepresence of a Lewis acid, such as aluminum chloride.

In addition, Stages 1 and 2 may be performed in reverse order to givecompounds of formula 2 that are ready to enter Stage 3. For instance,Friedel-Crafts acylation between a methyl ether (int 14) and anappropriately substituted acid chloride provides the ketone (int 16),which is simultaneously demethylated under the reaction conditions.Subsequent formation of the bridge —Y— via a nucleophilic aromaticdisplacement gives compounds of formula 2 that are ready to enter Stage3.

In stage 3, the Q function of compounds of formula 2 is converted intogroup G, which may be —C(Z)NR₁R₂, an aryl substituent, an arylthioether, or an appropriate heterocycle as defined herein, to givecompounds of formula 3. When the Q function of compounds of formula 2 isa halogen or trifluoromethanesulfonyloxy, it may be converted to an anester via alkoxycarbonylation using carbon monoxide, an aliphaticalcohol, a trialkanyl amine, and a palladium catalyst such asbis(triphenylphosphine) palladium(II)dichloride. Subsequently, when Q isan ester, the ester may be hydrolyzed to a carboxylic acid. Thecarboxylic acid may then be coupled with an appropriately functionalizedamine to form a primary, secondary or tertiary amide. Alternatively, theconversion of a carboxylic acid to an amide may be carried out via anacid chloride using thionyl chloride, oxalyl chloride, or the like,followed by a Schotten-Baumann reaction using an appropriatelyfunctionalized amine in the presence of an alkali metal hydroxide.Alternatively, the ester may be converted directly to the amide by theaction of a dimethylaluminum amide.

Instead of proceeding to compounds of formula 3 via an ester, one mayeffect the transformation of the group Q to a substituent G (wherein Gis an amidino or heterocycle) by way of a nitrile. Synthesis of thenitrile may be accomplished by treatment of the compounds of formula 2(when Q is bromo or trifluoromethanesulfonyloxy) with Zn(CN)₂ and apalladium catalyst such as (Ph₃P)₄Pd or by treatment of the compounds offormula 2 with CuCN at elevated temperatures. For the synthesis ofamidino functional groups, the nitrile is treated with hydroxylamineunder basic conditions to afford an oxime. Treatment of the oxime with aprimary or secondary amine, CuCl, and an alkali metal carbonate undermicrowave irradiation in an alcoholic solvent provides the amidinocompounds of the present invention. Microwave accelerated reactions maybe performed using either a CEM Discover or a Personal Chemistry SmithSynthesizer microwave instrument. The oxime described above isinstrumental in the preparation of compounds wherein G is a heterocycle.The oxime may be cyclized with a variety of electrophiles known to oneversed in the art to give the heterocycles of the present invention. Forinstance, reaction of an oxime with CDI provides oxadiazolones, andtreatment of the oxime with TCDI provides the correspondingoxadiazolethiones. Similarly, the treatment of the oxime with thionylchloride in the presence of a tertiary amine gives oxathiadiazoles ofthe present invention.

An aryl substituent may be installed in place of the functional group Qby coupling compounds of formula 2 (when Q is bromo ortrifluoromethanesulfonyloxy) with a suitably substituted arylboronicacid in the presence of a palladium catalyst and an alkali metalcarbonate.

To perform stage 4, an A-substituted ring is is attached to thetricyclic system, replacing the ketone to give compounds of formula 4wherein m is 0, 2, or 3, as defined herein. This operation may becarried out by McMurray condensation of ketones of formula 3 with4-piperidinones (m is 0) or 8-nortropinones (m is 2) or anazabicyclo(3.3.1)nonanone (m is 3), in the presence of a lower valenttitanium reagent. Such a reagent may be formed from the addition oftitanium tetrachloride to zinc dust. Alternatively, an appropriatelysubstituted magnesium halide may be added to ketones of formula 3 toafford carbinols. Dehydration of such carbinols with acidic reagentssuch as formic acid, sulfuric acid or trifluoroacetic acid also givesrise to compounds of formula 4. If desired, the operation of stages 3and 4 may be carried out in reverse order.

As illustrated in Schemes 1 and 2, the nitrogen atoms of compounds offormula 4 may bear a group P. This group may be an alkanyl, alkenyl oraralkanyl in which case they are the therapeutically useful products ofthis invention. The group P may also be trifluoromethylcarbonyl,alkoxycarbonyl or aralkoxycarbonyl. The latter groupings can beconverted to secondary amines of formula 5 as illustrated in Stage 5.These transformations may be carried out using certain acidic reagentssuch as hydrogen bromide or trimethylsilyl iodide. Or, when P is atrifluoromethylcarbonyl, basic reagents such as potassium carbonate inan alcoholic solvent may be used for the removal of P. Compounds offormula 4 bearing readily cleavable groups such as methyl, allyl orbenzyl may be transformed into the aforementioned alkoxycarbonylderivatives by treatment with alkanylchloro-formates such as ethylchloroformate or 1-chloroethyl chloroformate.

Finally, the secondary amines of formula 5 may be substituted with R₃ toprovide compounds of formula 6, shown in Stage 6. These transformationsmay be carried out by reductive alkylation using a carbonyl-containingcompound and a reducing agent such as sodium borohydride, sodiumcyanoborohydride, tetramethylammonium triacetoxyborohydride, or sodiumtriacetoxyborohydride. Substituent R₃ may also be installed via aconventional alkyation, using an alkanyl, alkenyl or aralkyl halide andan organic or inorganic base. One skilled in the art will recognize thatalkylating agents with leaving groups other than halide are equallyuseful for this transformation.

Desired end products of the present invention may include chemicalmodifications at R₄. Such transformations may include the dealkylationof lower alkyl ethers to give their corresponding alcohols, usingreagents such as boron trihalides. Compounds where R₄ is a halogen atommay participate in transition metal-mediated coupling reactions such asSuzuki, Stille or Negishi chemistry.

Scheme 4 demonstrates the preparation of compounds of the presentinvention wherein R₄ is other than hydroxy or mercapto. A compound offormula int 17 can be converted to its triflate by treatment withN,N-bis(trifluoromethylsulfonyl)phenylamine or similar reagents toafford a compound of formula int 18. Treatment of the triflate with acyanide source such as zinc cyanide in the presence of a palladiumcatalyst provides compounds of formula int 19, which subsequently can behydrolyzed with hydroxide anion in the presence of hydrogen peroxide toafford compounds of formula int 20 wherein R₄ is an aminocarbonyl.

The cyano group of a compound of formula int 19 is also a precursor toother R₄ substituents of the present invention. For example, a compoundof formula int 19 may be treated with ammonium hydroxide in the presenceof a base such as a tertiary amine to afford a hydroxyamidino compoundof formula int 21. Deprotection of compounds of formula int 21 affordscompounds of formula 5-1.

As illustrated in Scheme 5, a compound of formula int 18 may be treatedwith an amino synthon, where a synthon is a synthetic equivalent or afunctional group that is related to some other structural unit by areliable reaction or sequence of reactions. An example of an amino groupsynthon includes, but is not limited to, benzophenone imine.Benzophenone imine may be used in the presence of an appropriatepalladium catalyst under basic conditions, which upon treatment withammonium hydroxide, affords compounds of formula int 22. The aniline maybe formylated with acetic formic anhydride followed by removal of Pusing methods discussed herein. Lawesson's reagent may be used toconvert carbonyl-containing R₄ substituents to their correspondingthiocarbonyl analogs.

The preparation of compounds wherein R₄ is C₆₋₁₀arylamino may beachieved using a palladium catalyzed amination of a compound of formulaint 18 with C₆₋₁₀arylamine and an inorganic base, such as cesiumcarbonate.

Anilines of formula int 22 may be converted to the correspondingaminothiazoles of formula 6-2 via reaction with appropriate reagentssuch as potassium thiocyanate.

The compounds wherein the bridge -A- is —(CH₂)₂₋₃— are chiral. They maybe separated into their enantiomers by chromatography on a chiralstationary phase following Stages 4, 5, or 6. Alternatively, the basiccompounds of formulae 4, 5, and 6 may be converted to diastereomericsalts by mixture with a chiral acid and resolved into their enantiomersby fractional crystallization.

It is generally preferred that the respective product of each processstep be separated from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation. The structures of the final products, intermediates andstarting materials are confirmed by spectroscopic, spectrometric andanalytical methods including nuclear magnetic resonance (NMR), massspectrometry (MS) and liquid chromatography (HPLC). In the descriptionsfor the preparation of compounds of this invention, ethyl ether,tetrahydrofuran and dioxane are common examples of an ethereal solvent;benzene, toluene, hexanes and heptanes are typical hydrocarbon solventsand dichloromethane and dichloroethane are representative halogenatedhydrocarbon solvents. In those cases where the product is isolated asthe acid addition salt the free base may be obtained by techniques knownto those skilled in the art. In those cases in which the product isisolated as an acid addition salt, the salt may contain one or moreequivalents of the acid. Enantiomers of the compounds of the presentinvention may be separated using chiral HPLC.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described above and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art. Abbreviations CDI =1,1′-carbonyldiimidazole DBN = 1,8-diazabicyclo[5.4.0]undec-7-ene DMF =N,N-dimethylformamide dppf = 1,1′-bis(diphenylphosphino)ferrocene Et =ethyl h = hour(s) Me = methyl min = minute(s) TCDI =1,1′-thiocarbonyldiimidazole PPA = polyphosphoric acid t-Boc =tert-butoxycarbonyl TCDI = 1,1′-thiocarbonyldiimidazole TFA =trifluoroacetic acid THF = tetrahydrofuran μW = microwave irradiation W= watt(s)

EXAMPLES Example 1

Procedure A4-Bromo-2-phenoxybenzoic acid (1b).

4-Bromo-2-chloro-benzoic acid (10 g, 42 mmol), phenol (4.19 g, 44 mmol),tetrakisacetonitrilecopper hexafluorophosphate (3.95 g, 10.6 mmol), andcesium carbonate (27.6 g, 85 mmol) were added to a 1 L 3-neck roundbottom flask equipped with a mechanical stirrer, reflux condenser, andcontaining toluene (350 mL). The reaction was refluxed overnight undernitrogen with stirring. After cooling, ethyl acetate (200 mL) was addedand the reaction was acidified with aqueous 2N HCI. The organic phasewas separated, dried (MgSO₄), and filtered. The filtrate wasconcentrated to afford 4-bromo-2-phenoxybenzoic acid (12.4 g) that wasused in subsequent reactions without further purification.

Procedure B

3-Bromo-xanthen-9-one (1c).

Polyphosphoric acid (260 g, 20:1; w:w) was added to4-bromo-2-phenoxybenzoic acid (13.5 g). The reaction was heated (120°C.) while being stirred briskly with a mechanical stirrer to achievehomogeneity. After 2 h, the heating apparatus was removed. Once thereaction temperature was below 70° C., the mixture was poured overcrushed ice. The resulting aqueous solution was extracted withchloroform (3×100 mL). The combined organic extracts were washed withsodium bicarbonate solution (100 mL, 1 M), dried (MgSO₄), andconcentrated to afford 3-bromo-xanthen-9-one (11.4 g) that was used insubsequent reactions without further purification.

Procedure C

N-[2-(9-Oxo-9H-xanthen-3-yl)-phenyl]-acetamide (1d).

3-Bromo-xanthen-9-one (0.25 g, 0.9 mmol), 2-acetamidophenylboronic acid(0.99 mmol), 1,1′-bis-(diphenylphosphino)ferrocene-palladium (II)dichloride (33 mg, 0.045 mmol), cesium carbonate (0.59 g, 1.8 mmol),dioxane (4 mL), and ethanol (2 mL) were microwaved in a 5-mL reactionvessel at 100° C. for 5 min. The reaction was filtered and concentrated.The residue was purified by reverse phase chromatography to affordN-[2-(9-Oxo-9H-xanthen-3-yl)-phenyl]-acetamide.

Procedure D

N-{2-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-3-yl]-phenyl}-aceta-mide(Cpd 2).

A suspension of zinc powder (0.317 g, 4.8 mmol) in THF (100 mL) atambient temperature was treated with titanium(IV)chloride (0.266 mL, 2.4mmol) by dropwise addition. The resultant mixture was heated at refluxfor 2 h under a nitrogen atmosphere. The resultant solution was cooledto room temperature. A portion of3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(0.136 g, 0.6 mmol) and N-[2-(9-oxo-9H-xanthen-3-yl)-phenyl]-acetamide(0.20 g, 0.6 mmol) were added and the solution was heated at reflux for2 h. The reaction was diluted with ethyl acetate (15 mL) and aqueous 1 Nhydrochloric acid (20 mL). The organic layer was separated, dried(MgSO₄), and filtered. The filtrate was evaporated in vacuo. The crudeproduct was purified by reverse phase preparative HPLC, using a gradientof acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%),to give the trifluoroacetic acid salt of Compound 2 (0.124 g). MS m/z(MH⁺) 423.2; ¹H NMR (DMSO-d₆) δ1.32 (m, 2H), 1.79 (m, 2H), 1.88 (s, 3H),2.92-3.0 (m, 4H), 4.04 (m, 2H), 7.21-7.47 (m, 11H), 8.67 (bs, 1H), 9.05(d, 1H), 9.35 (s, 1H).

Example 2

3-(3-Pyridin-3-yl-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane (Cpd12).

The title compound was prepared using the method described in Example 1,substituting 3-pyridylboronic acid for 2-acetamidophenylboronic acid inProcedure C and using an adaptation of Procedure D. MS m/z (MH⁺) 367.1;¹H NMR (DMSO-d₆) δ 1.29 (d, 2H, J=9.2 Hz), 1.78 (m, 2H), 2.91-3.09 (m,4H), 4.01 (s, 2H), 7.24 (t, 1H, J=7.4 Hz), 7.31 (d, 1H, J=6.8 Hz), 7.38(d, 1H, J=7.0 Hz), 7.43 (d, 1H, J=7.7 Hz), 7.54 (d, 1H, J=8.0 Hz),7.62-7.73 (m, 2H), 7.73 (s, 1H), 8.32 (d, 1H, J=8.0 Hz), 8.68 (m, 1H),8.81 (m, 1H), 9.05 (s, 1H), 9.11 (m, 1H).

Example 3

2-Phenoxy-terephthalic acid dimethyl ester (3b).

The title compound was prepared according to the method described inProcedure A and substituting 2-iodo-terephthalic acid dimethyl ester for4-bromo-2-chloro-benzoic acid.

9-Oxo-9H-xanthene-3-carboxylic acid methyl ester (3c).

The title compound was prepared according to the method described inProcedure B, substituting 2-phenoxy-terephthalic acid dimethyl ester for4-bromo-2-phenoxybenzoic acid.

Procedure E

9-Oxo-9H-xanthene-3-carboxylic acid (3d).

A solution of 9-oxo-9H-xanthene-3-carboxylic acid methyl ester (3.75mmol) and 3 N sodium hydroxide (4.12 mmol) in MeOH (30 mL) was heated atreflux for 2 h. The solution was cooled to rt and made acidic with 2 Nhydrochloric acid. The mixture was concentrated in vacuo, and thendiluted with water. The resultant solid was collected by filtration,washed with water and air-dried to yield the title compound.

Procedure F

3-(Pyrrolidine-1-carbonyl)-xanthen-9-one (3e).

9-oxo-9H-xanthene-3-carboxylic acid (9 g, 37.4 mmol) was added tothionyl chloride (28 mL, 334 mmol). The mixture was refluxed for 5 h. Atthat time, the thionyl chloride was removed under vacuum and theremaining residue was diluted with toluene and concentrated to drynessto give 9-oxo-9H-xanthene-3-carbonyl chloride. A portion of9-oxo-9H-xanthene-3-carbonyl chloride (0.25 g, 0.96 mmol) was dissolvedin acetonitrile (7 mL). Diisopropylethylamine (335 μL, 1.9 mmol) wasthen added to the mixture with the subsequent addition of pyrrolidine(113 μL, 1.3 mmol). After stirring 2 h, the solvent was concentrated andthe residue was purified by reverse phase preparative HPLC, using agradient of acetonitrile (10%- 90%) in water with trifluoroacetic acid(0.1%) to afford the 3-(pyrrolidine-1-carbonyl)-xanthen-9-one. MS m/z(MH⁺) 294.1.

[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-3-yl]-pyrrolidin-1-yl-methanone(Cpd 6).

The title compound was prepared according to Procedure D, substituting3-(pyrrolidine-1-carbonyl)-xanthen-9-one forN-[2-(9-oxo-9H-xanthen-3-yl)-phenyl]-acetamide and obtained as a TFAsalt after reverse phase preparative HPLC. MS m/z (MH⁺) 387.2; ¹H NMR(DMSO-d₆) δ1.28 (d, 2H, J=11.2 Hz), 1.80-1.89 (m, 6H), 2.95 (q, 4H,J=16.1 Hz), 3.41 (t, 2H, J=6.2 Hz), 3.47 (t, 2H, J=6.8 Hz), 4.0 (s, 2H),7.23 (t, 1H, J=7.3 Hz), 7.28-7.46 (m, 6H), 8.80 (bs, 1 H), 9.11 (m, 1H).

Example 4

9-Oxo-9H-xanthene-3-carboxylic acid (2-hydroxy-ethyl)-methyl-amide (4a).

Using the method described in Procedure F, substituting2-methylamino-ethanol for pyrrolidine, the title compound 4a wasprepared.

3-{3-[(2-Hydroxyethyl)-methyl-carbamoyl]-xanthen-9-ylidene}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid ethyl ester (4b).

Using the method described in Procedure D, substituting9-Oxo-9H-xanthene-3-carboxylic acid (2-hydroxy-ethyl)-methyl-amide forN-[2-(9-oxo-9H-xanthen-3-yl)-phenyl]-acetamide and substituting3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester for3-oxo-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid tert-butyl ester,the desired product 4b was prepared.

Procedure G

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid(2-hydroxy-ethyl)-methyl-amide (Cpd 61).

A sample of compound 4b (0.20 g, 0.43 mmol) was dissolved in 1 mL aceticacid and 2 mL of 30% HBr in acetic acid was added to the reaction underArgon before heating at 80° C. for 1 h. The reaction was cooled, addedto ice cold NaOH and extracted with CHCl₃. The combined organic phaseswere concentrated. The resulting residue was purified by reverse phaseHPLC, using a gradient of acetonitrile (10% to 90%) in water withtrifluoroacetic acid (0.1%) to give the trifluoroacetic acid salt ofcompound 61 (0.146 g). MS m/z (MH⁺) 391.0; ¹H NMR (DMSO-d₆) δ1.26 (m,2H), 2.93-3.04 (m, 6H), 3.28 (m, 1H), 3.49 (m, 2H), 3.61 (m, 1H), 4.00(m, 3H), 7.21-7.42 (m, 1H, J=7.0 Hz), 8.65 (m, 1H), 9.05 (m, 1H).

Example 5

Procedure H8-(2,2,2-Trifluoroacetyl)-8-aza-bicyclo[3.2.1]octan-3-one (5b). To asolution of nortropinone hydrochloride (10 g, 61.87 mmol) and pyridine(20 mL, 247 mmol) in CH₂Cl₂ (120 mL) was added dropwise trifluoroaceticanhydride (12.4 mL, 87.79 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h and at room temperature for an additional 1 h.A portion of 2N HCl (65 mL) was added to the mixture. The organic phasewas washed with brine, dried (MgSO₄), and concentrated. The crudecompound 5b was used in the next reaction without further purification.MS m/z (MH⁺) 221.9; ¹H NMR (CDCl₃,) δ 1.78 (m, 1H), 1.90 (m, 1H), 2.19(m, 2H), 2.49 (d, 2H), 2.72 (m, 2H), 4.71 (m, 1H), 4.99 (m, 1H).Procedure I4-Bromo-2-phenoxy-benzonitrile (5c).

Sodium hydride (12 g, 300 mmol) (60% by wt) was weighed into a flask andwashed free of oil with several hexane rinsings. The hexanes weredecanted and discarded and DMF was added to the flask. A solution ofphenol (23.5 g, 250 mmol) in DMF (100 mL) was added dropwise and themixture was stirred at room temperature. To the mixture was added asolution of 4-bromo-2-fluoro-benzonitrile (50 g, 250 mmol, 100 mL DMF),dropwise. Upon complete addition, the reaction was refluxed for 20 h.The reaction was cooled to room temperature and poured into cold 1 NNaOH. A fine, tan precipitate formed and was collected by vacuumfiltration to give Compound 5c. MS m/z (MH⁺) 277.

Procedure J

4-Bromo-2-phenoxy-benzoic acid (1 b).

Compound 5c (35.3 g, 129 mmol) was added to 130 mL EtOH, followed by theaddition of 340 mL of 20% aqueous NaOH. The reaction was heated toreflux for 20 h. At that time the mixture was cooled to room temperatureand poured into 6 N HCl. The solid was collected by vacuum filtration,dissolved in 3:1 THF-ethyl ether, and washed with brine. The organicphase was dried (MgSO₄) and concentrated. The solids were dried in avacuum oven at 60° C. overnight to give the desired compound 1b. MS m/z(MH⁺) 292.

Procedure K

3-Bromo-xanthen-9-one (1c).

To a suspension of 4-bromo-2-phenoxy-benzoic acid (5 g, 17 mmol) inCH₂Cl₂ (50 mL) was added dropwise trifluoroacetic anhydride (2.9 mL,20.53 mmol) at room temperature. The mixture was stirred at roomtemperature for 5 min. To this solution was added dropwise borontrifluoride diethyl etherate (0.215 mL, 1.7 mmol) at 0° C. After 30 min,the reaction was allowed to warm to room temperature. The mixture wasstirred at room temperature for 2 h, at which time the mixture waspoured into 1 N NaOH (35 mL) that was cooled to about 3° C. The aqueouslayer was extracted with CH₂Cl₂ (2×10 mL). The combined organic layerswere washed with brine, dried (MgSO₄) and concentrated. Heptane wasadded to the residue and the resulting solid was collected by filtrationto give Compound 1c. MS m/z (MH⁺) 276.7; ¹H NMR (CDCl₃,) δ 7.43 (t, 1H),7.52 (m, 2H), 7.76 (m, 2H), 8.23 (d, 1H), 8.35 (dd, 1H).

1-[3-(3-Bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone (5d).

Using the method described in Procedure D, substituting Compound 1c forN-[2-(9-Oxo-9H-xanthen-3-yl)-phenyl]-acetamide and substituting Compound5b for 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester, the title compound 5d was prepared. MS m/z (MH⁺) 463.6, 465.8; ¹HNMR(CDCl₃,) δ1.43 (m, 2H), 1.82 (m, 2H), 2.94 (m, 4H), 4.42 (m, 1H),4.72 (m, 1H), 7.20 (m, 6H), 7.4 (m, 1H).

Procedure L

9-[8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carbonitrile (5e).

To a solution of Compound 5d (3 g, 6.46 mmol) in DMF (100 mL) was addedCuCN (0.69 g, 7.70 mmol). The reaction mixture was refluxed for 2 d andthen cooled to room temperature. The mixture was poured into water (100mL), and extracted with EtOAc (3×100 mL). The combined organic layerswere washed sequentially with H₂O (100 mL), brine (100 mL), then dried(MgSO₄) and concentrated. The crude product was purified by normal phasechromatography, using a gradient of ethyl acetate (0% to 10%) in heptaneto give compound 5e. MS m/z (M+H⁺) 410.9; ¹H NMR (CDCl₃) δ 1.41 (m, 2H),1.85 (m, 2H), 2.96 (m, 4H), 4.44 (m, 1H), 4.73 (m, 1H), 7.23 (m, 3H),7.33 (m, 2H), 7.43 (dt, 1H), 7.51 (m, 1H).

Procedure M

2,2,2-Trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone(5f).

To a solution of Compound 5e (0.232 g, 0.56 mmol) in DMF (5 mL) wereadded NaN₃ (0.11 g, 1.69 mmol) and NH₄Cl (0.09 g, 1.68 mmol). Thereaction mixture was heated at 120° C. for 14 h, and then cooled to roomtemperature. An insoluble material was collected by filtration andwashed with DMF (5 mL). The filtrate was acidified with 2N HCl (10 mL)and extracted with EtOAc (3×10 mL). The combined organic layers werewashed with H₂O (10 mL), dried (MgSO₄), and concentrated to give thetitle compound 5f which was used for subsequent reactions withoutfurther purification. MS m/z (MH⁺) 453.9.

Procedure N

3-[3-(1H-Tetrazol-5-ly)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1 ]octane(Cpd 1).

To a solution of Compound 5f (0.2 g, 0.44 mmol) in CH₃OH (4 mL) and H₂O(1 mL) was added K₂CO₃ (0.152 g, 1.1 mmol). The mixture was stirred atroom temperature for 14 h, and was purified by reverse phase HPLC togive the title Compound 1 as a TFA salt. MS m/z (MH⁺) 357.9; ¹H NMR(DMSO-d₆,) δ 1.27 (m, 2H), 1.77 (m, 2H), 2.97 (m, 4H), 4.00 (m, 2H),7.36 (m, 4H), 7.63 (d, 1H), 7.91 (m, 3H), 8.82 (m, 1H), 9.17 (m, 1H).

Example 6

Procedure ON-Hydroxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxamidine (6a).

To a suspension of compound 5e (0.44 g, 1.07 mmol) in EtOH (5 mL) wereadded NH₂OH.HCl (0.223 g, 3.19 mmol) and K₂CO₃ (0.3 g, 2.17 mmol). Thereaction mixture was refluxed for 4 h. Upon cooling to room temperature,H₂O (1 mL) was added to the mixture. The mixture was extracted withCH₂Cl₂ (2×5mL), dried (MgSO₄), and concentrated to yield compound 6a.The product 6a was used in the next reaction without furtherpurification. MS m/z (MH⁺) 443.9.

Procedure P

3-{9-[8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-3-yl}-4H-[1,2,4]oxadiazol-5-one (6b).

To a solution of compound 6a (0.1 g, 0.23 mmol) in 1,4-dioxane (4 mL)was added 1,1′-carbonyldiimidazole (CDl, 0.055 g, 0.34 mmol). Themixture was stirred at 110° C. for 40 min under a nitrogen atmosphere.After being cooled, the reaction was concentrated. The crude compound 6bwas used in the next reaction without further purification. MS m/z (MH⁺)469.8.

Procedure Q

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-3-yl]-4H-[1,2,4]oxadiazol-5-one (Cpd 4).

Using an adaptation of the method described in Procedure N andsubstituting compound 6b for compound 5f, the title compound 4 wasprepared as a TFA salt. MS m/z (MH⁺) 374.0; ¹H NMR (CH₃OH-d₄) δ 1.48 (m,2H), 1.94 (m, 2H), 3.11 (m, 4H), 4.06 (m, 2H), 7.26 (m, 2H), 7.38 (m,2H), 7.51 (d, 1H), 7.62 (m, 3H).

Example 7

2,2,2-Trifluoro-1-{3-[3-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone(7a).

Using an adaptation of Procedure P, substituting1,1′-thiocarbonyidiimidazole (TCDI) for CDI and adding1,8-diazabicyclo[5.4.0]undec-7-ene (DBN, 1 equivalent), the titlecompound 7a was prepared. The crude compound 7a was used in the nextreaction without further purification. MS m/z (MH⁺) 485.8.

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-3-yl]-4H-[1,2,4]oxadiazole-5-thione (Cpd 5).

Using an adaptation of the method described in Procedure N andsubstituting compound 7a for compound 5f, the title compound 5wasprepared as a TFA salt. MS m/z (MH⁺) 389.9; ¹H NMR (CH₃OH-d₄) δ 1.47 (m,2H), 1.93 (m, 2H), 3.10 (m, 4H), 4.06 (m, 2H), 7.27 (m, 2H), 7.37 (m,2H), 7.53 (d, 1H), 7.67 (m, 3H).

Example 8

Procedure R2,2,2-Trifluoro-1-{3-[3-(2-oxo-2,3-dihydro-2|4-[1,2,3,5]oxathiadiazol-4-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone(8a).

To a solution of compound 6a (0.071 g, 0.16 mmol) and pyridine (0.026mL, 0.32 mmol) in CH₂Cl₂ (1 mL) was added dropwise a solution of thionylchloride (0.013 mL, 0.18 mmol) in CH₂Cl₂ (1 mL) at −70° C. After beingstirred for 1 h at -70° C., the mixture was allowed to warm to roomtemperature, and then washed sequentially with water and brine, dried(MgSO₄), and concentrated. The resulting compound 8a was used in thenext reaction without further purification. MS m/z (MH⁺) 489.7.

3-[3-(2-Oxo-2,3-dihydro-2|4-[1,2,3,5]oxathiadiazol-4-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane (Cpd 10).

Using an adaptation of the method described in Procedure N andsubstituting compound 8a for compound 5f, the title compound 10 wasprepared as a TFA salt. MS m/z (MH⁺) 393.9; ¹H NMR (CH₃OH-d₄ δ 1.49 (m,2H), 1.94 (m, 2H), 3.11 (m, 4H), 4.06 (m, 2H), 7.28 (m, 2H), 7.39 (m,2H), 7.54 (d, 1H), 7.70 (m, 3H).

Example 9

Procedure S3-{9-[8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-3-yl}-4H-[1,2,4]thiadiazol-5-one (9a).

A mixture of compound 6a (0.0417 g, 0.094 mmol) and TCDI (0.025 g, 0.14mmol) in THF (2 mL) was stirred at room temperature for 45 min. Themixture was diluted with H₂O (2 mL) and extracted with EtOAc (3×5 mL).The combined organic extracts were washed with H₂O (15 mL), dried(MgSO₄), and concentrated. The residue was dissolved in THF (2 mL).Boron trifluoride diethyl etherate was added to the solution, and theresulting mixture was stirred at room temperature for 1 h. The mixturewas diluted with H₂O (2 mL) and extracted with EtOAc (3×5mL). Theorganic layers were dried (MgSO₄), and concentrated. The resultantcompound 9a was used in the next reaction without further purification.MS m/z (MH⁺) 485.8.

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-3-yl]-4H-[1,2,4]thiadiazol-5-one (Cpd 8).

Using an adaptation of the method described in Procedure N andsubstituting compound 9a for compound 5f, the title compound 8 wasprepared as a TFA salt. MS m/z (MH⁺) 389.9; ¹H NMR (CH₃OH-d₄,) δ 1.48(m, 2H), 1.93 (m, 2H), 3.11 (m, 4H), 4.05 (m, 2H), 7.27 (m, 2H), 7.38(m, 2H), 7.50 (d, 1H), 7.76 (m, 3H).

Example 10

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-N,N-diethyl-9H-xanthene-3-carboxamidine (Cpd 9).

A mixture of compound 5e (0.06 g, 0.146 mmol), diethylamine (0.766 mL,7.31 mmol) and Cu(I)Cl (0.0724 g, 0.731 mmol) in MeOH (1 mL) wereexposed to microwave irradition (300 W) at 140° C. for 20 min. A portionof K₂CO₃ (0.2 g, 1.45 mmol) was added to the reaction mixture andstirred at room temperature for 3 h. The solid was collected by vacuumfiltration, and the crude product was purified by reverse phase HPLC togive compound 9 as a TFA salt. MS m/z (MH⁺)387.9; ¹H NMR (CH₃OH-d₄) δ1.22 (t, 3H), 1.39 (t, 3H), 1.48 (d, 2H), 1.96 (m, 2H), 3.12 (m, 4H),3.42 (q, 2H), 3.7 (q, 2H), 4.07 (m, 2H), 7.28 (m, 2H), 7.40 (m, 3H),7.53 (d, 1H), 7.61 (d, 1H).

Example 11

Procedure TAcetic hydrazide benzenesulfonic acid (11a).

To a solution of acetic hydrazide (2g, 27.0 mmol) in EtOH (5 mL) wasadded benzenesulfonic acid (4.7g, 29.7 mmol) in small portions. A whitesolid formed. A volume of Et₂O (5 mL) was added to the mixture. Theresulting solid was collected by filtration, washed with Et₂O, and driedto give compound 11a. ¹H NMR (D₂O) δ 1.95 (s, 3H), 7.45 (m, 3H), 7.75(d, 2H).

Procedure U

3-[3-(5-Methyl-4H-[1,2,4]triazol-3-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane(35).

A mixture of compounds 11a (0.029 g, 0.125 mmol) and 5e (0.051g, 0.124mmol) was exposed to microwave irradition (300 W) at 200° C. for 10 min.After cooling, MeOH (1 mL) and 1N NaOH (1 mL) were added to the reactionmixture and the mixture was stirred at rt for 30 min. The crude productwas purified by reverse phase HPLC to yield compound 35 as a TFA salt.MS m/z (MH⁺) 371.0; ¹H NMR (CH₃OH-d₄) δ 1.40 (d, 2H), 1.85 (m, 2H), 1.41(s, 3H), 3.02 (m, 4H), 3.91 (m, 2H), 7.19 (m, 4H), 7.33 (d, 2H), 7.84(d, 1H), 7.85 (s, 1H).

Example 12

Procedure V9-[8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxamidine (12a).

To a solution of n-BuLi (2.5M in hexanes, 0.487 mL, 1.22 mmol) in Et₂O(1 mL) was added dropwise a solution of 1,1,1,3,3,3-hexamethyldisilazane(0.257 mL, 1.22 mmol) in Et₂O (1 mL) at 0° C. The mixture was stirred at0° C. for 30 min. Compound 5e (0.2g, 0.49 mmol) was added to the mixtureand the mixture was stirred at rt for 2 h. The mixture was poured intoice-cold 2N HCl (2 mL) and extracted with Et₂O (2×3 mL). The aqueousphase was adjusted to pH ˜8 with 1 N NaOH and extracted with CH₂Cl₂ (2×3mL). The organic layers were combined, dried over MgSO₄, filtered, andconcentrated. The resultant compound 12a was used in the next reactionwithout further purification. MS m/z (MH⁺) 427.8.

Procedure W

3-[3-(5-Ethyl-1H-imidazol-2-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]-octane (Cpd26).

A mixture of compound 12a (0.050 g, 0.112 mmol), 1-bromo-2-butanone(0.012 g, 0.118 mmol) and NaHCO₃ (0.02 g, 0.238 mmol) in EtOH (1 mL)were exposed to microwave irradition (300 W) at 150° C. for 20 min.After cooling, 1N NaOH (0.5 mL) was added to the reaction mixture andthe mixture stirred at rt for 30 min. The crude product was purified byreverse phase HPLC to yield compound 26 as a TFA salt. MS m/z (MH⁺)384.0; ¹H NMR (CH₃OH-d₄) δ 1.39 (m, 3H), 1.52 (m, 2H), 1.96 (m, 2H),2.83 (q, 2H), 3.15 (m, 4H), 4.09 (m, 2H), 7.30 (m, 2H), 7.43 (m, 3H),7.63 (m, 1H), 7.72 (m, 1H), 7.85 (m, 1H).

Example 13

Procedure X2,2,2-Trifluoro-1-{3-[3-(1-methyl-1H-tetrazol-5-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone (13a) and2,2,2-Trifluoro-1-{3-[3-(2-methyl-2H-tetrazol-5-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone(13b).

A mixture of compound 5f (0.16 g, 0.35 mmol), methyl iodide (0.044 mL,0.71 mmol) and potassium carbonate (0.24 g, 1.74 mmol) in acetone (8 mL)was heated to reflux (oil bath, 60° C.) for 2 h. The mixture was allowedto cool to rt, and the solid was removed via filtration. The solvent wasremoved in vacuo. The mixture of crude products 13a and 13b was used inthe next reaction without further purification. MS m/z (MH⁺) 467.9.

3-[3-(1-Methyl-1H-tetrazol-5-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane (Cpd 21)and3-[3-(2-Methyl-2H-tetrazol-5-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane(Cpd 16). Using an adaptation of the method described in Procedure N andsubstituting the mixture of compounds 13a and 13b for compound 5f, amixture of the title compounds 21 and 16 were prepared. Compounds 21 and16 were separated and purified via reverse phase HPLC as their TFAsalts. Cpd 21: MS m/z (MH⁺) 371.9; ¹H NMR (CH₃OH-d₄,) δ 1.52 (d, 2H),1.97 (m, 2H), 3.15 (m, 4H), 4.08 (m, 2H), 4.27 (s, 3H), 7.29 (m, 2H),7.41 (m, 2H), 7.67 (m, 2H), 7.76 (d, 1H). Cpd 16: MS m/z (MH⁺) 371.9; ¹HNMR (CH₃OH-d₄,) δ 1.52 (d, 2H), 1.95 (m, 2H), 3.12 (m, 4H), 4.06 (m,2H), 4.45 (s, 3H), 7.24 (m, 2H), 7.37 (m, 2H), 7.53 (d, 1H), 7.96 (m,2H).

Example 14

Procedure Y3-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane(Cpd 36).

A mixture of Compound 6a (0.046 g, 0.104 mmol) and NaH (60% in oil,0.0042 mg, 0.105 mmol) in THF (4 mL) was refluxed for 1 h. Aftercooling, acetic acid methyl ester (0.0082 mL, 0.103 mmol) was added tothe mixture. The mixture was stirred at reflux temperature overnight.The mixture was poured into ice-cold water and extracted with CH₂Cl₂(2×5 mL). The organic phase was washed with H₂O , dried over MgSO₄, andconcentrated. The crude product was purified by reverse phase HPLC togive Compound 36 as a TFA salt. MS m/z (MH⁺) 371.9; ¹H NMR (CH₃OH-d₄,) δ1.52 (d, 2H), 1.95 (m, 2H), 2.66 (s, 3H), 3.12 (m, 4H), 4.05 (m, 2H),7.23 (m, 1H), 7.31 (m, 1H), 7.39 (m, 2H), 7.52 (d, 1H), 7.83 (d, 1H),7.84 (s, 1H).

Example 15

4-Bromo-2-phenylsulfanyl-benzonitrile (15a) and2,4-Bis-phenylsulfanyl-benzonitrile (15b).

Using the method described in Procedure I, substituting benzenethiol forphenol, a mixture of the title compounds 15a and 15b were prepared. Themixture was separated via normal phase chromatography (eluent gradient:0 to 20% EtOAc in heptane) to yield Compounds 15a and 15b. Compound 15a:MS m/z (MH⁺) 291.8; Compound 15b: MS m/z (MH⁺) 319.8.

4-Bromo-2-phenylsulfanyl-benzoic acid (15c).

Using the method described in Procedure J, substituting Compound 15a forCompound 5c, Compound 15c was prepared. MS m/z (MH⁺) 308.7.

3-Bromo-thioxanthen-9-one (15d).

Using the method described in Procedure K, substituting Compound 15c forCompound 1b, Compound 15d was prepared. MS m/z (MH⁺) 290.7.

1-[3-(3-Bromo-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone (15e).

Using the method described in Procedure D, substituting Compound 15d forN-[2-(9-oxo-9H-xanthen-3-yl)-phenyl]-acetamide and substituting Compound5b for 3-oxo-8-aza-bicyclo-[3.2.1]carboxylic acid tert-butyl ester,Compound 15e was prepared. MS m/z (MH⁺) 481.6.

3-(3-Bromo-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1 ]octane (84).

Using the method described in Procedure N, substituting Compound 15e forCompound 5f, the title compound 84 was prepared as a TFA salt. MS m/z(MH⁺) 385.6; ¹H NMR (DMSO-d₆,) δ 1.27 (m, 2H), 1.77 (m, 2H), 2.97 (m,4H), 4.00 (m, 2H), 7.36 (m, 4H), 7.63 (d, 1H), 7.91 (m, 3H), 8.82 (m,1H), 9.17 (m, 1H).

Example 16

3-(3-Phenylsulfanyl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane(16a).

Using the method described in Procedure J, substituting Compound 15b forCompound 5c, the title compound 16a was prepared. MS m/z (MH⁺) 338.7.

3-Phenylsulfanyl-thioxanthen-9-one (16b).

Using the method described in Procedure K, substituting Compound 16a forCompound 1b, Compound 16b was prepared. MS m/z (MH⁺) 320.9.

2,2,2-Trifluoro-1-[3-(3-phenylsulfanyl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone(16c).

Using the method described in Procedure D, substituting Compound 16b forN-[2-(9-oxo-9H-xanthen-3-yl)-phenyl]-acetamide and substituting Compound5b for 3-oxo-8-aza-bicyclo-[3.2.1] carboxylic acid tert-butyl ester,Compound 16c was prepared. MS m/z (MH⁺) 509.7.

3-(3-Phenylsulfanyl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1 ]octane(83).

Using the method described in Procedure N, substituting Compound 16c forCompound 5f, the title compound 83 was prepared as a TFA salt. MS m/z(MH⁺) 413.7; ¹H NMR (CH₃OH-d₄,) δ 1.32 (m, 2H), 1.76 (m, 2H), 2.74 (m,4H), 3.84 (m, 2H), 7.25 (m, 11 H), 7.41 (d, 1 H).

Example 17

9-[8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9Hthioxanthene-3-carbonitrile (17a).

Using the method described in Procedure L, substituting Compound 15e forCompound 5d, the title compound 17a was prepared. MS m/z (MH⁺) 426.7; ¹HNMR (CDCl₃) δ 1.41 (m, 2H), 1.83 (m, 2H), 2.76 (m, 4H), 4.40 (m, 1H),4.70 (m, 1H), 7.33 (m, 4H), 7.56 (m, 2H), 7.51 (s, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-thioxanthene-3-carbonitrile(85).

Using the method described in Procedure N, substituting Compound 17a forCompound 5f, the title compound 85 was prepared. MS m/z (MH⁺) 330.9; ¹HNMR (CH₃OH-d₄) δ 1.33 (m, 2H), 1.81 (m, 2H), 2.78 (m, 4H), 3.91 (m, 2H),7.21 (m, 3H), 7.38 (d, 1H), 7.49 (d, 1H), 7.57 (dd, 1H), 7.85 (d, 1H).

Example 18

9-[(1RS,5SR)-8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-thioxanthene-3-carbonitrile(18a) and9-[(1SR,5RS)-8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-thioxanthene-3-carbonitrile(18b).

Racemic Compound 17a was separated via chiral chromatography into itsenantiomers using a Chiralpack AD column (500 g) and a 1:1heptane:ethanol eluent mixture (UV monitoring at 220 nm and flow rate of80 mL/min), yielding Compounds 18a (first eluting isomer) and 18b(second eluting isomer).

2,2,2-Trifluoro-1-{3-[3-(1tetrazol-5-yl)-thioxanthen-9-ylidene]-[(1RS,5SR)-8-aza-bicyclo[3.2.1]oct-8-yl}]-ethanone(18c) and2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-thioxanthen-9-ylidene]-[(1SR,5RS)-8-aza-bicyclo[3.2.1]oct-8-yl}]-ethanone(18d).

Using the method described in Procedure M, substituting Compound 18a forCompound 5e, the title compound 18c was prepared. MS m/z (MH⁺) 469.8.Similarly, using the method described in Procedure M, substitutingCompound 18b for Compound 5e, the title compound 18d was prepared.

(1RS,5SR)-3-[3-(1H-Tetrazol-5-yl)-thioxanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane(Cpd 102) and(1SR,5RS)-3-[3-(1H-tetrazol-5-yl)-thioxanthen-9-ylidene]-8-aza-bicyclo[3.2.1]octane(Cpd 103).

Using the method described in Procedure N, substituting Compound 18c forCompound 5f, the title compound 102 was prepared as a TFA salt. MS m/z(MH⁺) 373.8; ¹H NMR (CH₃OH-d₄) δ 1.37 (m, 2H), 1.79 (m, 2H), 2.84 (m,4H), 3.89 (m, 2H), 7.25 (m, 3H), 7.43 (d, 1H), 7.50 (d, 1H), 7.91 (dd,1H), 8.13 (d, 1H). Similarly, using the method described in Procedure N,substituting Compound 18d for Compound 5f, the title compound 103 wasprepared as a TFA salt.

Example 19

Procedure Z2,2,2-Trifluoro-1-[3-(3-pyridin-3-yl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone(19a)

To a suspension of compound 15e (0.3 g, 0.625 mmol), cesium carbonate(0.51 g, 1.565 mmol) and 3-pyridineboronic acid (0.0844 g, 0.687 mmol)in dioxane (4 mL) and EtOH (1 mL) was added1,1′-bis-(diphenylphosphino)-ferrocene-palladium (II) dichloride (46 mg,0.063 mmol). The mixture was heated at 90° C. for 3 hrs, and cooled toroom temperature. The solid was filtreted, and washed with CH₃OH (10 mL)and H₂O (10 mL). The filtrate was concentrated under reduce pressure toafford crude product. The crude product 19a was used in the nextreaction without further purification. MS m/z (MH⁺) 479.0.

3-(3-Pyridin-3-yl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane (Cpd112).

Using the method described in Procedure N, substituting Compound 19a forCompound 5f, the title compound 112 was prepared as a TFA salt. MS m/z(MH⁺) 383.3; ¹H NMR (CDCl₃) δ 1.50 (m, 2H), 2.02 (m, 2H), 2.80 (t, 2H),3.12 (m, 2H), 4.00 (m, 2H), 7.31 (m, 3H), 7.42 (d, 2H), 7.55 (dd, 1H),7.78 (s, 1H), 7.92 (dd, 1H), 8.40 (d, 1H), 8.76 (d, 1H), 9.08 (s, 1H).

Example 20

Procedure AA8-Furan-3-ylmethyl-3-(3-pyridin-3-yl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane(116)

A mixture of compound 112 (20 mg, 0.04 mmol), 3-furaldehyde (13.5 mg,0.156 mmol) and tetramethylammonium triacetoxyborohydride (16 mg, 0.061mmol) in dichloroethane (2 mL) was stirred at 80° C. overnight in asealed tube. The solvent was removed under reduced prossure. The crudeproduct was purified by reverse phase HPLC to give compound 116 as a TFAsalt. MS m/z (MH⁺) 463.2; ¹H NMR (CD₃CN) δ 1.45 (d, 2H), 2.06 (m, 2H),2.90 (m, 2H), 3.80 (m, 2H), 3.98 (m, 2H), 6.69 (s, 1H), 7.35 (m, 3H),7.48 (d, 1H), 7.61 (m, 4H), 7.78 (m, 1H), 7.96 (s, 1H), 8.41 (d, 1H),8.75 (d, 1H), 9.01 (s, 1H).

Example 21

4-Bromo-2-(2-methoxy-phenoxy)-benzonitrile (21b).

Using the method described in Procedure I, substituting 2-methoxyphenolfor phenol, the title compound 21b was prepared. MS m/z (MH⁺) 303.8,305.8.

4-Bromo-2-(2-methoxy-phenoxy)-benzoic acid (21c).

Using the method described in Procedure J, substituting Compound 21b forCompound 5c, the title compound 21c was prepared. MS m/z (MH⁺) 322.8,324.7.

3-Bromo-5-methoxy-xanthen-9-one (21d).

Using the method described in Procedure K, substituting Compound 21c forCompound 1b, the title compound 21d was prepared. MS m/z(MH⁺) 304.8,306.7.

1-[3-(3-Bromo-5-methoxy-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone (21e).

Using the method described in Procedure D, substituting Compound 21d forCompound 1c and substituting Compound 5b for3-oxo-8-aza-bicyclo[3.2.1]-octane-8-carboxylic acid tert-butyl ester,the title compound 21e was prepared. MS m/z (MH⁺) 467.7, 469.7.

5-Methoxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carbonitrile(21f).

Using the method described in Procedure L, substituting Compound 21e forCompound 5d, the title compound 21e was prepared. MS m/z (M+23) 462.7.

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-methoxy-9H-xanthen-3-yl]-4H-[1,2,4]oxadiazol-5-one(21g).

Using the method described in Procedure O, substituting Compound 21f forCompound 5e, the title compound 21 g was prepared. MS m/z (MH⁺) 473.9.

3-{5-Methoxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-3-yl}-4H-[1,2,4]oxadiazol-5-one(21h).

Using the method described in Procedure P, substituting Compound 21g forCompound 6a, the title compound 21h was prepared. MS m/z (MH⁺) 499.8.

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-methoxy-9H-xanthen-3-yl]-4H-[1,2,4]oxadiazol-5-one(132).

Using the method described in Procedure N, substituting Compound 21h forCompound 5f, the title compound 132 was prepared as a TFA salt. MS m/z(MH⁺) 403.9; ¹H NMR (DMSO-d₆) δ 1.28 (m, 2H), 1.79 (m, 2H), 2.98 (m,4H), 3.90 (s, 3H), 4.03 (m, 2H), 6.98 (d, 1H), 7.10 (d, 1H), 7.19 (t,1H), 7.65 (m, 2H), 7.74 (s, 1H).

Example 22

Procedure BB3-{5-Hydroxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-3-yl}-4H-[1,2,4]oxadiazol-5-one(22a).

To a solution of Compound 21h (0.355 g, 1.19 mmol) in CH₂Cl₂ (30 mL) wasadded dropwise BBr₃ (1.0M in CH₂Cl₂, 5.97 mL, 5.97 mmol) at 0° C. Themixture was stirred at rt for 24 h, and quenched with a saturated NaHCO₃solution (20 mL). The organic layer was dried over MgSO₄ andconcentrated. The crude product was used in the next reaction withoutfurther purification. MS m/z (MH⁺) 485.8.

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-hydroxy-9H-xanthen-3-yl]-4H-[1,2,4]oxadiazol-5-one(134).

Using the method described in Procedure N, substituting Compound 22a forCompound 5f, the title compound 134 was prepared as a TFA salt. MS m/z(MH⁺) 389.9; ¹H NMR (CH₃OH-d₄) δ 1.43 (m, 2H), 1.82 (m, 2H), 2.95 (m,2H), 3.22 (t, 2H), 3.94 (m, 2H), 6.75 (m, 2H), 7.00 (t, 1H), 7.42 (d,1H), 7.51 (dd, 1H), 7.65 (s, 1H).

Example 23

2,2,2-Trifluoro-1-{3-[5-methoxy-3-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone(23a)

Using the method described in Procedure P, substituting Compound 21g forCompound 6a, substituting 1,1′-thiocarbonyldiimidazole (TCDI) for CDIand adding 1,8-diazabicyclo[5.4.0]undec-7-ene (DBN, 1 equivalent), thetitle compound 23a was prepared. MS m/z (MH⁺) 515.8.

3-[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-methoxy-9H-xanthen-3-yl]-4H-[1,2,4]oxadiazole-5-thione(133).

Using the method described in Procedure N, substituting Compound 23a forCompound 5f, the title compound 133 was prepared as a TFA salt. MS m/z(MH⁺) 419.9; ¹H NMR (DMSO-d₆) δ 1.26 (m, 2H), 1.78 (m, 2H), 2.93 (m,2H), 3.32 (t, 2H), 3.90 (s, 3H), 4.00 (m, 2H), 6.98 (t, 1H), 7.10 (t,1H), 7.28 (t, 1H), 7.58 (d, 1H), 7.81 (d, 1H), 7.90 (s, 1H).

Example 24

Procedure CC3,6-Dihydroxy-xanthen-9-one (24a).

Following a procedure disclosed in the literature, (Janjic, N. et al. J.Am. Chem. Soc. 1989, 111, 6374-6375) compound 24a was prepared. MS m/z(MH⁺) 228.9.

Procedure DD

Trifluoro-methanesulfonic acid9-oxo-6-trifluoromethane-sulfonyloxy-9H-xanthen-3-yl ester (24b).

Compound 24a (1.18 g, 5.18 mmol) was suspended in 30 mL ofdichloromethane, treated with pyridine (836 mL), and stirred at rt for10 min. Upon cooling to 0 C., triflic anhydride (1.73 mL, 10.3 mmol) wasadded dropwise. The mixture was stirred at 0 C. for 1 h and then allowedto warm to rt with additional stirring overnight. Upon completion of thereaction the mixture was concentrated under reduced pressure. Theresultant residue was purified by normal phase chromatography usingdichloromethane as eluant to give compound 24b. MS m/z (MH⁺) 492.6.

Procedure EE

9-Oxo-9H-xanthene-3,6-dicarboxylic acid dimethyl ester (24c).

Compound 24b (0.52 g, 1.06 mmol) and DIEA (553 μL) were added to amixture of DMF:MeOH (1:1, 20 mL total volume) and the flask was purgedwith Argon gas. The mixture was then treated with Pd(dppf)Cl₂ (43 mg,0.053 mmol), purged, then charged with carbon monoxide and heated to 75C. for 8 h. The mixture was cooled to rt and concentrated under reducedpressure at 50 C. The resultant residue was taken up in CH₂Cl₂, andwashed sequentially with 1 N HCl, saturated aqueous NaHCO₃, and brine.The organic phase was partitioned, dried over magnesium sulfate,filtered, and the filtrate was concentrated to a residue. The residuewas purified by normal phase chromatography using a gradient of 0.1 to0.4% MeOH in dichloromethane as eluant to give compound 24c.

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3,6-dicarboxylic aciddimethyl ester (78).

The title compound was prepared according to Procedure D, substituting9-oxo-9H-xanthene-3,6-dicarboxylic acid dimethyl ester forN-[2-(9-oxo-9H-xanthen-3-yl)-phenyl]-acetamide.

Compounds 1 through 134 of Formula (Ia) (wherein R₅ is H and A is CH₂CH₂), in the table below were synthesized using the procedures describedabove. Formula (Ia)

Cpd G R₃ R₄ Y 1 1H-tetrazol-5-yl H H O 2 2-methylcarbonyl H H Oaminophenyl 3 N-(2-dimethylamino-eth-1- ethoxy H O yl)-N-methyl-carbonyl aminocarbonyl 4 4H-[1,2,4]-oxadiazol-5-oxo- H H O 3-yl 54H-[1,2,4]-oxadiazol-5- H H O thioxo-3-yl 6 pyrrolidin-1-ylcarbonyl H HO 7 N-(2-methoxy-ethyl)-N- H H O methyl-aminocarbonyl 84H-[1,2,4]thiadiazol-5-oxo- H H O 3-yl 9 N,N-diethylamidino H H O 10[1,2,3,5]oxathiadiazol-2- H H O oxo-4-yl 11 N-(3-fluorophenyl)-methyl- HH O aminocarbonyl 12 pyridin-3-yl H H O 13 N-[2-(2,6- H H Odimethylphenoxy)-1- methyl-ethyl] aminocarbonyl 14 N-phenyl-N-methyl- HH O aminocarbonyl 15 N-(1(S)-hydroxymethyl-2- H H O phenyl-eth-1-yl)aminocarbonyl 16 2-methyl-tetrazol-5-yl H H O 17 N-(2-phenylethyl)-N-H H O methyl-aminocarbonyl 18 2-aminocarbonyl-phenyl H H O 192-phenylethyl- H H O aminocarbonyl 20 3-methylcarbonylamino- H H Ophenyl 21 1-methyl-tetrazol-5-yl H H O 22 N-cyclohexyl-N-methyl H H Oaminocarbonyl 23 3-hydroxymethyl-phenyl H H O 24 N-hydroxyamidino H H O25 2-aminophenyl H H O 26 5-ethyl-1H-imidazol-2-yl H H O 27N-(1(R)-hydroxymethyl-2- H H O phenyl-eth-1-yl) aminocarbonyl 28N,N-diisobutylamidino H H O 29 pyridin-4-yl H H O 304-methylcarbonylamino- H H O phenyl 31 N-(1S-methoxymethyl-2- H H Ophenyl-eth-1- yl)aminocarbonyl 32 2-methoxypyridin-5-yl H H O 334,5-dihydro-1H- H H O imidazol-2-yl 34 N-(4-phenyl)-cyclohexyl- H H Oaminocarbonyl 35 3-methyl-4H-[1,2,4] H H O triazol-5-yl 365-methyl-[1,2,4] H H O oxadiazol-4-yl 37 N-(1(S)-hydroxymethyl-1- H H Omethoxycarbonyl)amino carbonyl 38 3-hydroxy-phenyl H H O 39isopropylamidino H H O 40 phenylmethylamino H H O carbonyl 411,4,5,6-tetrahydro H H O pyrimidin-2-yl 42 4-aminophenyl H H O 43C-piperidin-1-yl- H H O methyleneamine 44 2-methoxyphenyl H H O 45cyclopentylaminocarbonyl H H O 46 3-methylphenyl H H O 47phenylaminocarbonyl H H O 48 N,N-bis(2,2,2-trifluoro- H H Oeth-1-yl)aminocarbonyl 49 isobutylamidino H H O 50 C-morpholin-4-yl- H HO methyleneamine 51 3-fluorophenyl H H O 52 N-benzyl-N-methyl- H H Oaminocarbonyl 53 4-methanesulfonyl-phenyl H H O 54 4-fluorophenyl H H O55 thiophen-3-yl H H O 56 N-(2-dimethylamino-eth-1- H H O yl)-N-methyl-aminocarbonyl 57 3-methoxyphenyl H H O 58 phenylmethylamino ethoxy H Ocarbonyl carbonyl 59 phenylaminocarbonyl ethoxy H O carbonyl 60cyclopentylaminocarbonyl ethoxy H O carbonyl 61 N-(2-hydroxy-ethyl)-N- HH O methyl-aminocarbonyl 62 N-[(4-trifluoromethyl)- H H Ocyclohexyl]-aminocarbonyl 63 3-methanesulfonylamino- H H O phenyl 64N-2,2,2,-trifluoroethyl- H H O aminocarbonyl 65 3-[(3-methoxy)phenyl H HO ]piperidin-1-ylcarbonyl 66 N-4-fluorophenyl-N-methyl- H H Oaminocarbonyl 67 N-(1(R)-hydroxymethyl-3- H H O methyl-but-1-yl)-aminocarbonyl 68 N-(dimethylamino H H O carbonylmethyl)-N-methyl-aminocarbonyl 69 (3(R)-hydroxy) H H O pyrrolidin-1-ylcarbonyl 70(3(S)-hydroxy) H H O pyrrolidin-1-ylcarbonyl 71 pyridin-3-yl H 5-methoxyO 72 carboxy H H O 73 methoxycarbonyl H H O 74 methoxycarbonyl ethoxy HO carbonyl 75 N-(2-hydroxy-ethyl)-N- ethoxy H O methyl-aminocarbonylcarbonyl 76 methoxycarbonyl H H S 77 cyano H H O 78 methoxycarbonyl H6-methoxy O carbonyl 79 bromo H 5-methoxy O 80 1H-tetrazol-5-yl H H O 811H-tetrazol-5-yl H H O 82 1H-tetrazol-5-yl H 5-methoxy O 83 phenylthio HH S 84 bromo H H S 85 cyano H H S 86 cyano H H O 87 cyano H H O 88 cyanotrifluoro H O methyl carbonyl 89 cyano trifluoro H O methyl carbonyl 901H-tetrazol-5-yl H 5-hydroxy O 91 4H-[1,2,4]-oxadiazol-5-oxo- H H O 3-yl92 4H-[1,2,4]-oxadiazol-5-oxo- H H O 3-yl 93 4H-[1,2,4]-oxadiazol-5- H HO thioxo-3-yl 94 4H-[1,2,4]-oxadiazol-5- H H O thioxo-3-yl 954H-[1,2,4]thiadiazol-5-oxo- H H O 3-yl 96 methoxycarbonyl H H O 97N-(2-hydroxy-1,1-dimethyl- H H O ethyl)-aminocarbonyl 98 carboxyt-butoxy H O carbonyl 99 carboxy H H O 100 carboxy H H O 1014H-[1,2,4]thiadiazol-5-oxo- H H O 3-yl 102 1H-tetrazol-5-yl H H S 1031H-tetrazol-5-yl H H S 104 quinolin-3-yl H 5-methoxy O 105 fur-3-yl H5-methoxy O 106 thien-3-yl H 5-methoxy O 107 pyridin-4-yl H 5-methoxy O108 2-methylcarbonylamino- H 5-methoxy O phenyl 109 quinolin-3-yl H5-hydroxy O 110 N-(2-hydroxy-ethyl) H H O aminocarbonyl 1111-methyl-pyrazol-3-yl H H O 112 pyridin-3-yl H H S 1132-methylcarbonylamino- H H S phenyl 114 pyridin-3-yl methyl H S 115pyridin-3-yl 1H-imidazol H S 2-ylmethyl 116 pyridin-3-yl fur-3-ylmethylH S 117 pyridin-3-yl pyridin-2-yl H S methyl 118 2-methylcarbonylamino-methyl H S phenyl 119 2-methylcarbonylamino- 1H-imidazol H S phenyl2-ylmethyl 120 2-methylcarbonylamino- fur-3-yl H S phenyl methyl 1212-methylcarbonylamino- pyridin-2-yl H S phenyl methyl 122N-(2-hydroxy-ethyl)- t-butoxy H O aminocarbonyl carbonyl 123N-(2-hydroxy-ethyl)- H H O aminocarbonyl 124 N-(2-hydroxy-ethyl)-N- H HO methyl-aminocarbonyl 125 N,N-diethylamidino H H O 126N,N-diethylamidino H H O 127 (3(R)-hydroxy) H H Opyrrolidin-1-ylcarbonyl 128 pyridin-3-yl trifluoro H O methyl carbonyl129 pyridin-3-yl trifluoro H O methyl carbonyl 130 2-methylcarbonyltrifluoro H O aminophenyl methyl carbonyl 131 2-methylcarbonyl trifluoroH O aminophenyl methyl carbonyl 132 4H-[1,2,4]- H 5-methoxy Ooxadiazol-5-oxo-3-yl 133 4H-[1,2,4]- H 5-methoxy Ooxadiazol-5-thioxo-3-yl 134 4H-[1,2,4]- H 5-hydroxy Ooxadiazol-5-oxo-3-yl

BIOLOGICAL EXAMPLES Example 1 Rat Brain Delta Opioid Receptor BindingAssay

Procedure: Male, Sprague Dawley rats (150-250 g, VAF, Charles River,Kingston, N.Y.) were killed by CO₂, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainswere separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains werehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate was diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet wasresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation was used for the delta opioid binding assays. Followingincubation with the delta selective peptide ligand ˜4 nM [³H]DPDPE at25° C. for 2.5 h in a 96-well plate with total volume of 1 mL, the platecontents were filtered through Wallac filtermat B sheets on a Tomtec96-well harvester. The filters were rinsed three times with 2 mL of 10mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 mintwice. To each sample area 2×50 μL of Betaplate Scint scintillationfluid (LKB) was added and the radioactivity quantified on a LKB (Wallac)1205 BetaPlate liquid scintillation counter.

Analysis: The data from the scintillation counter were used to calculateeither the % inhibition compared to control binding (when only a singleconcentration of test compound was evaluated) or a K_(i) value (when arange of concentrations was tested). Percent inhibition was calculatedas: [(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kdand Ki values were calculated using GraphPad PRISM data analysisprogram.

Example 2 Rat Brain Mu Opioid Receptor Binding Assay

Procedure: Male, Sprague Dawley rats (150-250 g, VAF, Charles River,Kingston, N.Y.) were killed by CO₂, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainswere separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains werehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate was diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet wasresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation was used for the delta opioid binding assays. Followingincubation with the mu selective peptide ligand, ˜0.8 nM [³H]DAMGO, at25° C. for 2.5 h in a 96-well plate with total assay volume of 1 mL, theplate contents were filtered through Wallac filtermat B sheets on aTomtec 96-well harvester. The filters were rinsed three times with 2 mLof 10 mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75min twice. To each sample area 2×40 μL of Betaplate Scint scintillationfluid (LKB) was added and the radioactivity quantifed on a LKB (Wallac)1205 BetaPlate liquid scintillation counter.

Analysis: The data from the scintillation counter were used to calculateeither the % inhibition compared to control binding (when only a singleconcentration of test compound was evaluated) or a K_(i) value (when arange of concentrations tested). Percent inhibition was calculated as:[(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kd andKi values were calculated using GraphPad PRISM data analysis program.

Example 3 [³⁵S]GTPγS Binding Assay in NG108-15 Cell Membranes (deltaopioid)

Methods: NG108-15 cell membranes were purchased from Applied CellSciences (Rockville, Md.). 8 mg/mL of membrane protein suspended in 10mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. Membranes were maintained at4-8° C. A 1 mL volume of membranes was added into 10 mL cold bindingassay buffer. The assay buffer contained 50 mM Tris, pH 7.6, 5 mM MgCl₂,100 mM NaCl, 1 mM DTT and 1 mM EGTA. The membrane suspension washomogenized twice with a Polytron, and centrifuged at 3000 rpm for 10min. The supernatant was then centrifuged at 18,000 rpm for 20 min. TenmL assay buffer was added into the pellet containing tube. The pelletand buffer were mixed with a Polytron.

Incubation procedure: The pellet membranes (75 μg/mL) were preincubatedwith SPA (10 mg/mL) at 25° C. for 45 min in the assay buffer. The SPA (5mg/mL) coupled with membranes (37.5 pg/mL) was then incubated with 0.1nM [³⁵] GTPγS in the same Tris buffer containing 100 μM GDP in totalvolume of 200 μL. Increasing concentrations of receptor agonists wereused to stimulate [35S]-GTPγS binding. The basal binding was tested inthe absence of agonists and non-specific binding was tested in thepresence of 10 μM unlabeled GTPγS. The data were analyzed on a PackardTop Count.

DATA

% of Basal=(stimulated−non specific)*100/(basal−non specific). EC₅₀value values were calculated using GraphPad Prism.

Example 4 [³⁵]GTPγS Binding Assays in CHO-hMOR Cell Membranes

Methods: CHO-hMOR cell membranes were purchased from Receptor Biology,Inc. (Baltimore, Md.). About 10 mg/mL of membrane protein was suspendedin 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose, and the suspensionkept on ice. A 1 mL volume of membranes was added to 15 mL cold bindingassay buffer containing 50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1mM DTT and 1 mM EDTA. The membrane suspension was homogenized with aPolytron and centrifuged at 3,000 rpm for 10 min. The supernatant wasthen centrifuged at 18,000 rpm for 20 min. The pellet was resuspended in10 mL assay buffer with a Polytron. The membranes were preincubated withwheat germ agglutinin coated SPA beads (Amersham) at 25° C. for 45 minin the assay buffer. The SPA bead (5 mg/mL) coupled membranes (10 μg/mL)were then incubated with 0.5 nM [³⁵S]GTPγS in the assay buffer. Thebasal binding was that taking place in the absence of added testcompound; this unmodulated binding was considered as 100%, with agoniststimulated binding rising to levels significantly above this value. Arange of concentrations of receptor agonist was used to stimulate[35S]GTPγS binding. Both basal and non-specific binding was tested inthe absence of agonist; non-specific binding determination included 10μM unlabeled GTPγS.

Compounds were tested for function as antagonists by evaluating theirpotential to inhibit agonist-stimulated GTPγS binding. Radioactivity wasquantified on a Packard TopCount. The following parameters werecalculated:${\%\quad{stimulation}} = {\frac{\left( {{{test}\quad{compound}\quad{cpm}} - {{non}\text{-}{specific}\quad{cpm}}} \right)}{\left( {{{basal}\quad{cpm}} - {{non}\text{-}{specific}\quad{cpm}}} \right)} \times 100.}$${\%\quad{inhibition}} = {\frac{\begin{matrix}\left( {{\%\quad{stimulation}\quad{by}\quad 1\quad{µM}\quad{DAMGO}} -} \right. \\\left. {\%\quad{stimulation}\quad{by}\quad{test}\quad{compound}} \right)\end{matrix}}{100} \times \left( {{\%\quad{stimulation}\quad{by}\quad 1\quad{µM}\quad{DAMGO}} - 100} \right)}$

EC₅₀ values were calculated using GraphPad Prism. Biological and MassSpectral Data Par- DOR hMOR ent Cpd DOR Ki MOR Ki GTPγS GTPγS peak MSNo. (nM) (nM) EC₅₀ (nM) EC₅₀ (nM) obs calcd 1 1.99 637 189/70.3 357.9357.42 2 4.36 1136 394.0 423.2 422.53 3 10000 10000 490.4 489.62 4 6.78768 128.0 374.0 373.41 5 6.89 1017 104.0 389.9 389.48 6 7.40 1396 59.0387.2 386.49 7 7.63 1815 173.0 405.2 404.51 8 10.79 1083 359.0 389.9389.48 9 14 3537 387.9 387.53 10 15.15 819 393.9 393.46 11 18.52 739209.0 441.3 440.52 12 24 2132 587.0 0.47 367.1 366.46 13 23.57 2922641.0 495.6 494.63 14 27.10 1157 423.2 422.53 15 27.48 414 79.0 467.3466.58 16 30 1458 573.0 0.48 371.9 371.44 17 37.01 37 451.2 450.58 18 381537 409.2 408.50 19 44.99 438 437.4 436.55 20 46.58 2802 423.5 422.5321 54 1743 371.9 371.44 22 54.90 1124 429.5 428.58 23 75 3507 396.4395.50 24 76.83 621 347.9 347.42 25 77.42 1665 381.2 380.49 26 81 249384.0 383.49 27 100.33 100 467.1 466.58 28 107.45 3103 444.0 443.63 29133 1817 367.0 366.46 30 139 2738 423.3 422.53 31 142.33 660 481.5480.61 32 160 10000 397.2 396.49 33 223.50 315 357.9 357.46 34 246.876237 491.5 490.65 35 266 673 371.0 370.46 36 373 3550 371.9 371.44 37412.14 950 435.3 434.49 38 418 706 382.2 381.47 39 441.15 5169 374.0373.50 40 456.10 3087 423.4 422.53 41 464.15 875 372.0 371.48 42 4901314 381.2 380.49 43 496.07 5341 399.9 399.54 44 659 7583 396.1 395.5045 673.20 3099 401.4 400.52 46 723 10000 380.1 379.50 47 812.60 1197409.4 408.50 48 938.60 2061 496.45 49 1325.85 4019 388.0 387.53 501757.50 14910 402.0 401.51 51 2445 16470 384.4 383.47 52 2732.95 1831437.2 436.55 53 3144 3290 444.1 443.56 54 4470 10000 384.3 383.47 554724 9282 372.2 371.50 56 4929.75 28456 417.9 417.55 57 6958 19660 396.1395.50 58 10000 10000 495.3 494.59 59 10000 10000 481.1 480.56 60 473.6472.58 61 6.25 876 391.0 390.48 62 309 7400 483.5 482.55 63 161 5120459.4 458.58 64 52 411 415.4 414.43 65 88 317 507.5 506.65 66 93 935441.5 440.52 67 360 1568 433.4 432.56 68 8.5 2389 5960/98.8  0.0 431.5469 105 2060 403.4 402.49 70 63 1660 403.3 402.49 71 5.7 1145 1940.0396.49 72 216 1960 333.39 73 1008 6345 347.41 74 — — 419.48 75 446810000 462.55 76 370 4743 363.48 77 2707 2476 314.39 78 1152 7002 405.4579 191.7 4776 398.30 80 87.1/1.38 7523/2571 226.0 357.9 357.42 81 0.5261 183/17.1 357.9 357.42 82 5.6 307 88.4 387.44 83 8506 >10000 413.7413.60 84 2899.0 >10000 258.6 384.34 85 628.6 2311 330.9 330.45 86 — —314.9 314.39 87 — — 314.9 314.39 88 — — 410.7 410.39 89 — — 410.7 410.3990  13/0.4 0.7/6.0 0.7 90 373.42 91 0.76 >10000 72.2 373.8 373.41 920.07 502 102.0 374 373.41 93 0.37 3744 631.0 389.9 389.48 94 0.04 219126.0 389.9 389.48 95 159 4928 389.9 389.48 96 — — 347.41 97 266 1895404.51 98 — — 433.50 99 — — 333.39 100 — — 333.39 101 7.0 465 281.0389.9 389.48 102 54 2771 373.8 373.48 103 10.1 329 49.6 373.8 373.48 104246 1713 446.55 105 88 497 385.46 106 281 2744 401.53 107 106 597 396.49108 33.9 426 117.0 452.55 109 2.22 31 94.2 1226 432.52 110 — — 377.2376.46 111 220 2645 370.2 369.47 112 481 1011 383.3 382.53 113 90 1518439.2 438.59 114 108 109 397.2 396.56 115 91 60 463.2 462.62 116 93 113463.2 462.61 117 95 97 474.1 473.64 118 612 2071 453.1 452.62 119 142349 519.3 518.68 120 54 183 519.2 518.68 121 3.7 137 530.2 529.71122 >10000 >10000 476.57 123 106 1016 376.46 124 >10000 >10000 491.2490.60 125 6.3 2049 78.3 >10,000 388.2 387.53 1261414 >10000 >10,000 >10,000 388.2 387.53 127 191 907 403.2 402.49128 >10000 >10000 463.2 462.47 129 >10000 >10000 463.2 462.47130 >10000 >10000 519.2 518.53 131 >10000 >10000 519.2 518.53 132 0.32254 403.9 403.44 133 2.37 371 419.9 419.50 134 0.12 2 389.9 389.41DOR Ki: Rat delta opioid receptor binding constantMOR Ki: Rat mu opioid receptor binding constant

Example 5 Rat CFA Radiant Heat Model of Inflammatory Pain

Interplanar injection of Complete Freund's Adjuvant (CFA) in rodentsresults in long-lasting inflammatory reaction, characterized by achronic and a strong, hyperalgesia to both thermal and mechanicalstimuli. These effects peak between 24-72 h following injection, and canlast for several days to a few weeks. To assess the ability of compoundsto reverse thermal hyperalgesia, male Sprague-Dawley rats (200-350 g)are given an intraplantar injection of CFA (1:1 CFA:saline, 100 μL) intotheir left hindpaw. Following a 24-h incubation period, responselatencies on the Radiant Heat Paw Stimulator (RH) are obtained andcompared to baseline (pre-CFA) latencies. The RH device automaticallyregisters lifting of the paw from the surface of the glass. Only ratsthat exhibit at least a 25% reduction in response latency from baseline(i.e. hyperalgesia) are included in further analysis. Following the postCFA latency assessment, rats are dosed orally (2.5 mL/kg) with testcompound or vehicle (hydroxypropylmethylcellulose, HPMC). Percentreversal of hyperalgesia is calculated for each animal as (TreatmentResponse−postCFA Response)/(preCFA Response−postCFA Response)×100.Therefore, a return to normal pre-CFA thresholds is defined as 100%efficacy, whereas no change from post-CFA thresholds is 0% efficacy.Average % reversal of hyperalgesia is then calculated for each treatmentgroup (n=6-8 rats/group).

Example 6

The therapeutic effect of delta opioid agonists has been demonstratedin:

Pain (Fang, (1995) Shengli Kexue Jinzhan 26:137-40; Garzon, (1995)Analgesia (Elmsford, N.Y) 1:131-44; Matthes, Maldonado, Simonin,Valverde, Slowe, Kitchen, Befort, Dierich, Le Meur and et al., (1996)Nature (London) 383:819-823; Stevens, (1996) Journal of Pharmacology andExperimental Therapeutics 276:440-8; Dondio, Ronzoni and Petrillo,(1997) Expert Opinion on Therapeutic Patents 7:1075-1098; Hutcheson,Sanchez-Blazquez, Rodriguez-Diaz, Garzon, Schmidhammer, Borsodi, Roquesand Maldonado, (1999) European Journal of Pharmacology 383:29-37;Fraser, Pradhan, Clarke and Wahlestedt, (2000) Journal of Pharmacologyand Experimental Therapeutics 295:1135-1141; Scheideler, (2000) CurrentOpinion in Central & Peripheral Nervous System Investigational Drugs2:171-177; Wei, Brown, Takasaki, Plobeck, Delorme, Zhou, Yang, Jones,Gawell, Gagnon, Schmidt, Yue, Walpole, Payza, St-Onge, Labarre, Godbout,Jakob, Butterworth, Kamassah, Morin, Projean, Ducharme and Roberts,(2000) Journal of Medicinal Chemistry 43:3895-3905; Nagase, Yajima,Fujii, Kawamura, Narita, Kamei and Suzuki, (2001) Life Sciences68:2227-2231; Abeyta, Dettmer, Barnes, Vega, Carta, Gallegos,Raymond-Stintz, Savage, Valenzuela and Saland, (2002) Brain Research931:100-5. FIELD Reference Number: FIELD Journal Code:0045503 FIELD CallNumber:; Cahill, Morinville, Hoffert, O'Donnell and Beaudet, (2003) Pain101:199-208; Collina, Azzolina, Vercesi, Brusotti, Rossi, Barbieri,Lanza, Mennuni, Alcaro, Battaglia, Linati and Ghislandi, (2003) Farmaco58:939-946; Hurley, Banfor and Hammond, (2003) Neuroscience (Oxford,United Kingdom) 118:789-796).

Inflammatory Pain States

(Stein, Millan, Shippenberg, Peter and Herz, (1989) Journal ofPharmacology and Experimental Therapeutics 248:1269-75; Antonijevic,Mousa, Schaefer and Stein, (1995) Journal of Neuroscience 15:165-72;Ballet, Mauborgne, Benoliel, Bourgoin, Hamon, Cesselin and Collin,(1998) Brain Research 796:198-208; Hurley and Hammond, (2001) Journal ofNeuroscience 21:2536-2545; Przewlocki and Przewlocka, (2001) EuropeanJournal of Pharmacology 429:79-91; Spetea, Rydelius, Nylander, Ahmed,Bileviciute-Ljungar, Lundeberg, Svensson and Kreicbergs, (2002) EuropeanJournal of Pharmacology 435:245-252; Bao, Jin, Zhang, Wang, Xu, Zhang,Wang, Ning, Cai, Guan, Xiao, Xu, He, Hokfelt, Zhou and Zhang, (2003)Neuron 37:121-133; Cahill, Morinville, Hoffert, O'Donnell and Beaudet,(2003) Pain 101:199-208; Martin, Matifas, Maldonado and KiefferBrigitte, (2003) European Journal of Neuroscience 17:701-8. FIELDReference Number: FIELD Journal Code:8918110 FIELD Call Number:;Petrillo, Angelici, Bingham, Ficalora, Garnier, Zaratin, Petrone, Pozzi,Sbacchi, Stean, Upton, Dondio and Scheideler, (2003) Journal ofPharmacology and Experimental Therapeutics 307:1079-1089).

Visceral Pain

(Schmauss and Yaksh, (1984) Journal of Pharmacology and ExperimentalTherapeutics 228:1-12; Craft, henley, Haaseth, Hruby and Porreca, (1995)Journal of Pharmacology and Experimental Therapeutics 275:1535-42; Su,Wachtel and Gebhart, (1998) Journal of Neurophysiology 80:3112-3119;Gebhart, Su, Joshi, Ozaki and Sengupta, (1999) Progress in Pain Researchand Management 14:225-235; Sora, Li, Funada, Kinsey and Uhl, (1999)European Journal of Pharmacology 366:R3-R5; Gebhart, (2000) RegionalAnesthesia and Pain Medicine 25:632-638; Martin, Matifas, Maldonado andKieffer Brigitte, (2003) European Journal of Neuroscience 17:701-8).

Lung

(Kuo, Rohde, Barnes and Rogers, (1992) British Journal of Pharmacology105:361-6; Campa, Schreiber, Bepler, Bishop, McNutt, Chang and Patz,(1996) Cancer Research 56:1695-701; Bolli, Shinmura, Tang, Kodani, Xuan,Guo and Dawn, (2002) Cardiovascular Research 55:506-519; Janssens,Leenaerts, Fernandez-Gadea, Gomez-Sanchez, Flameng, Herijgers, Meert andBorgers, (2003) PCT Int. Appl. 75 pp.; McLeod, Tulshian and Hey, (2003)Expert Opinion on Therapeutic Patents 13:1501-1512).

Cardioprotection

(Schultz, Hsu, Nagase and Gross, (1998) American Journal of Physiology274:H909-H914; Fryer, Hsu, Eells, Nagase and Gross, (1999) CirculationResearch 84:846-851; Fryer, Hsu, Nagase and Gross, (2000) Journal ofPharmacology and Experimental Therapeutics 294:451-457; Fryer, Hsu andGross, (2001) Basic Research in Cardiology 96:136-142; Fryer, Patel, Hsuand Gross, (2001) American Journal of Physiology 281 :H 184-H1192;Fryer, Pratt, Hsu and Gross, (2001) Journal of Pharmacology andExperimental Therapeutics 296:642-649; Fryer, Wang, Hsu and Gross,(2001) American Journal of Physiology 280:H1346-H1353; Fryer, Wang, Hsu,Nagase and Gross, (2001) Journal of Pharmacology and ExperimentalTherapeutics 299:477-482; Huh, Gross, Nagase and Liang, (2001) AmericanJournal of Physiology 280:H377-H383; Karck, Tanaka, Bolling, Simon, Su,Oeltgen and Haverich, (2001) Journal of Thoracic and CardiovascularSurgery 122:986-992; McPherson and Yao, (2001) Anesthesiology94:1082-1088; Patel, Hsu, Moore and Gross, (2001) Journal of Molecularand Cellular Cardiology 33:1455-1465; Rebrova, Maslov and Tam, (2001)Voprosy Meditsinskoi Khimii 47:338-345; Patel, Ludwig, Fryer, Hsu,Warltier and Gross, (2002) FASEB Journal 16:1468-1470,10.1096/fj.02-0170fje; Sigg, Coles, Oeltgen and laizzo, (2002) AmericanJournal of Physiology 282:H1953-H1960; Zhang, McPherson, Liu, Baman,McPherson, Rock and Yao, (2002) Journal of Pharmacology and ExperimentalTherapeutics 301:1012-1019; Patel, Hsu and Gross, (2004) Basic Researchin Cardiology 99:38-45; Patel, Hsu and Gross, (2004) Life Sciences75:129-140; Pear and Gross, (2004) Basic research in cardiology99:29-37. FIELD Reference Number: FIELD Journal Code:0360342 FIELD CallNumber; Shinmura, Nagai, Tamaki and Bolli, (2004) Basic research incardiology 99:46-55.

Urinary Dysfunction

(Dray and Metsch, (1984) Neuroscience Letters 47:81-4; Dray, (1985)Journal of Pharmacological Methods 13:157-65; Craft, henley, Haaseth,Hruby and Porreca, (1995) Journal of Pharmacology and ExperimentalTherapeutics 275:1535-42; Murase, Hamada and Asaki, (1996) PCT Int.Appl. 93 pp.; Su, Sengupta and Gebhart, (1997) Journal ofNeurophysiology 77:1566-1580; Sezen, Kenigs and Kapusta, (1998) Journalof Pharmacology and Experimental Therapeutics 287:238-245; Chang, Gengo,Biciunas, Ma, Pendergast and Jan, (2003) PCT Int. Appl. 73 pp.; Igari,Yanai and Goya, (2004) PCT Int. Appl. 30 pp.).

Cough

(Kamei, Iwamoto, Suzuki, Nagase, Misawa and Kasuya, (1993) EuropeanJournal of Pharmacology 234:117-20; Kotzer, Hay, Dondio, Giardina,Petrillo and Underwood, (2000) Journal of Pharmacology and ExperimentalTherapeutics 292:803-9; McLeod, Tulshian and Hey, (2003) Expert Opinionon Therapeutic Patents 13:1501-1512).

Anxiety

(Roberts, Gold, Polis, McDonald, Filliol, Kieffer and Koob, (2001)Alcoholism: Clinical and Experimental Research 25:1249-1256;Gaveriaux-Ruff and Kieffer, (2002) Neuropeptides (Edinburgh, UnitedKingdom) 36:62-71; Masuda, Suzuki, Takemura, Sugawara, Guo, Liu,Kawarada, Shimizu and Sugiyama, (2003) Tohoku Journal of ExperimentalMedicine 201:23-27; Noble and Roques, (2003) Drugs of Today 39:897-908).

Depression

(Broom, Jutkiewicz, Folk, Traynor, Rice and Woods, (2002)Psychopharmacology (Berlin, Germany) 164:42-48; Broom, Jutkiewicz, Folk,Traynor, Rice and Woods, (2002) Neuropsychopharmacology 26:744-755;Broom, Jutkiewicz, Rice, Traynor and Woods, (2002) Japanese Journal ofPharmacology 90:1-6; Varona, Gil, Saracibar, Maza, Echevarria andIrazusta, (2003) Arzneimittel-Forschung 53:21-25).

Parkinsons Disease

(Barneoud, Descombris, Aubin and Abrous, (2000) European journal ofneuroscience 12:322-36. Hill, Hille and Brotchie, (2000) Drug News &Perspectives 13:261-268; Hudzik, Howell, Payza and Cross, (2000)European Journal of Pharmacology 396:101-107; Hille, Fox, Maneuf,Crossman and Brotchie, (2001) Experimental Neurology 172:189-198).

Example 7

The therapeutic effect of mu opioid agonists has been demonstrated in:

Pain

(Pasternak, (1986) Advances in Pain Research and Therapy 8:337-44;Garzon and Sanchez-Blazques, (1995) Life Sciences 56:PL237-PL242;Matthes, Maldonado, Simonin, Valverde, Slowe, Kitchen, Befort, Dierich,Le Meur and et al., (1996) Nature (London) 383:819-823; Stevens, (1996)Journal of Pharmacology and Experimental Therapeutics 276:440-8; Dayer,Desmeules and Collart, (1997) Drugs 53:18-24; Valverde, Maldonado andKieffer, (1998) CNS Drugs 10:1-10; Kharkevich and Churukanov, (1999)European Journal of Pharmacology 375:121-131; Pasternak, (2000) Progressin Pain Research and Management 16:147-162; Gutstein and Akil, J. G.Hardman and L. E. Limbird (2001) The pharmacological basis oftherapeutics 569-619; Pasternak, (2001) Neuroscientist 7:220-231; Smith,Ross, Nielsen and Saini, (2001) European Journal of Pain (London, UnitedKingdom) 5:135-136; Wells, Bartlett, Ananthan and Bilsky, (2001) Journalof Pharmacology and Experimental Therapeutics 297:597-605; Abbadie andPasternak, (2003) Handbook of Chemical Neuroanatomy 20:1-29; Collina,Azzolina, Vercesi, Brusotti, Rossi, Barbieri, Lanza, Mennuni, Alcaro,Battaglia, Linati and Ghislandi, (2003) Farmaco 58:939-946; Cowan,(2003) International Journal of Clinical Practice, Supplement 133:3-8;Hurley, Banfor and Hammond, (2003) Neuroscience (Oxford, United Kingdom)118:789-796; Neilan, King, Rossi, Ansonoff, Pintar, Schiller andPasternak, (2003) Brain Research 974:254-257; Porreca and Hruby, (2003)Pain 407-419; Servin, (2003) Advances in Experimental Medicine andBiology 523:245-260; Gilbert, Hosztafi, Mahurter and Pastemak, (2004)European Journal of Pharmacology 492:123-130).

Inflammatory Pain

(Gutstein and Akil, J. G. Hardman and L. E. Limbird (2001) Thepharmacological basis of therapeutics 569-619).

Immune Function

(Renaud and Tomer, (1996) Advances in Experimental Medicine and Biology402:63-69; Sacerdote, Bianchi, Manfredi and Panerai, (1997) Pain72:325-330; Carrigan, Saurer, Ijames and Lysle, (2004) InternationalImmunopharmacology 4:419-428).

Visceral Pain

(Kharkevich and Churukanov, (1999) European Journal of Pharmacology375:121-131; Gebhart, (2000) Regional Anesthesia and Pain Medicine25:632-638; Churukanov, (2003) Eksperimental'naya i KlinicheskayaFarmakologiya 66:24-31).

Esophageal Reflux

(Tonini, de Giorgio and de Ponti, (2004) Drugs 64:347-361).

Muscle Pain

Nielsen, Mathiesen and Blackburn-Munro, (2004) European Journal ofPharmacology 487:93-103).

Cancer Pain

9Gutstein and Akil, J. G. Hardman and L. E. Limbird (2001) Thepharmacological basis of therapeutics 569-619; Wells, Bartlett, Ananthanand Bilsky, (2001) Journal of Pharmacology and Experimental Therapeutics297:597-605; Valenzano, Miller, Chen, Shan, Crumley, Victory, Davies,Huang, Allie, Nolan, Rotshteyn, Kyle and Brogle, (2004) Journal ofPharmacology and Experimental Therapeutics 310:783-792).

Cough

(Gutstein and Akil, J. G. Hardman and L. E. Limbird (2001) Thepharmacological basis of therapeutics 569-619).

Example 8 Delta, Mu Analgesic Synergy

Delta and mu opioid agonists have been repeatedly demonstrated toproduce antinociceptive synergy: (Vaught and Takemori, (1979) Journal ofPharmacology and Experimental Therapeutics 211:280-3; Vaught andTakemori, (1979) Journal of Pharmacology and Experimental Therapeutics208:86-90; Porreca, Jiang and Tallarida, (1990) European Journal ofPharmacology 179:463-8; Sutters, Miakowski, Taiwo and Levine, (1990)Brain Research 530:290-4; Horan, Tallarida, Haaseth, Matsunaga, Hrubyand Porreca, (1992) Life Sciences 50:1535-41; Malmberg and Yaksh, (1992)Journal of Pharmacology and Experimental Therapeutics 263:264-75; Adams,Tallarida, Geller and Adler, (1993) Journal of Pharmacology andExperimental Therapeutics 266:1261-7; Dykstra, Schoenbaum, Yarbrough,McNutt and Chang, (1993) Journal of Pharmacology and ExperimentalTherapeutics 267:875-82; Rossi, Pasternak and Bodnar, (1994) BrainResearch 665:85-93; Negri, Improta, Lattanzi, Potenza, Luchetti andMelchiorri, (1995) British Journal of Pharmacology 116:2931-8; Dykstra,Granger, Allen, Zhang and Rice, (2002) Psychopharmacology (Berlin,Germany) 163:420-429).

Example 9 Delta, Mu Reduced Side Effect Profile

Combinations of delta and mu opioid agonists have demonstrated reducedside effect profiles including fewer convulsions, lower incidence ofstraub tail, and attenuated respiratory depression (O'Neill, Collins,Pettit, McNutt and Chang, (1997) Journal of Pharmacology andExperimental Therapeutics 282:271-277; Su, McNutt and Chang, (1998)Journal of Pharmacology and Experimental Therapeutics 287:815-823).

Therefore compounds dually embodying delta and mu opioid pharmacologieswill have greater analgesic action and a reduced side effect profilethan that derived from either sole pharmacology.

1. A compound of Formula (I):

wherein: G is —C(Z)NR₁R₂, C₆₋₁₀aryl, C₆₋₁₀arylthio, or a heterocycleselected from the group consisting of imidazolyl, triazolyl, tetrazolyl,oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl,tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl, triazinyl,furyl, indazolyl, indolyl, indolinyl, isothiazolyl, isoxazolyl,oxazolyl, isoxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, andpyridinyl; wherein the C₆₋₁₀aryl group in the C₆₋₁₀aryl-containingsubstituents of G and the heterocycles of G are optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy,hydroxy(C₁₋₈)alkanyl, carboxy(C₁₋₈)alkanyl, C₁₋₈alkanylcarbonylamino,halogen, hydroxy, cyano, nitro, oxo, thioxo, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl,C₁₋₈alkanylsulfonylamino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, C₁₋₈alkanylaminocarbonyl,di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino; R₁ is asubstituent selected from the group consisting of hydrogen, C₁₋₈alkanyl,C₂₋₈alkenyl, and C₂₋₈alkynyl; R₂ is a substituent selected from thegroup consisting of hydrogen; C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkynyl; C₆₋₁₀aryl; and C₃₋₈cycloalkanyl; provided that when Z is O or S, R₂ isother than hydrogen or unsubstituted C₁₋₈alkanyl; and, whereinC₁₋₈alkanyl of R₂ is optionally substituted with one to threesubstituents independently selected from the group consisting of phenyl,amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanyloxy,C₁₋₆alkanylthio, hydroxy, fluoro, chloro, cyano, aminocarbonyl,C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl,C₁₋₆alkanyloxycarbonyl, and aryloxy; wherein the phenyl and aryloxysubstituents of C₁₋₈alkanyl are further substituted with, and theC₆₋₁₀aryl and C₃₋₈cycloalkanyl substituents of R₂ are optionallysubstituted with, one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy, trifluoromethyl, trifluoromethoxy, phenyl, halogen,cyano, hydroxy, C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl, andC₁₋₈alkanylsulfonylamino; or R₁ and R₂ taken together with the nitrogento which they are attached form a 5-7 membered cycloheteroalkyloptionally substituted with phenyl (wherein phenyl is optionallysubstituted with one to three C₁₋₄alkanyl or C₁₋₄alkanyloxysubstituents) and one to two additional substituents independentlyselected from the group consisting of C₁₋₈alkanyl, hydroxy(C₁₋₈)alkanyl,hydroxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, and halogen; or,R₁ and R₂ taken together with the nitrogen to which they are attachedform a 5-7 membered cycloheteroalkyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, and halogen; R₃ is a substituent selected from thegroup consisting of hydrogen, C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and heteroaryl(C₁₋₈)alkanylwherein the heteroaryl is selected from the group consisting ofbenzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indazolyl,indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; whereinphenyl, naphthyl, and heteroaryl are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen,hydroxy, cyano, fluoro(C₁₋₆)alkanyl, thioureido, andfluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl and heteroaryl areoptionally substituted with alkanyl or alkanyloxy substituents attachedto adjacent carbon atoms, the two substituents can together form a fusedcyclic alkanyl or cycloheteroalkanyl selected from the group consistingof —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and —O(CH₂)₁₋₃O—; R₄ is one tothree substituents independently selected from the group consisting ofhydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl(C₂₋₆)alkynyl,C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl,aminocarbonyl, C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen,hydroxy, mercapto, aminothiocarbonyl, amidino, hydroxyamidino,phenylcarbonyl, —C(═NOH)phenyl, aminomethyl, hydroxymethyl,methanesulfonylamino, C₆₋₁₀arylamino (wherein C₆₋₁₀aryl is optionallysubstituted with one to three substitutents independently selected fromthe group consisting of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy),dihydroimidazolyl, formylamino, thioformylamino, pyridinylamino, cyano,hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl,fluoroalkanyl and fluoroalkanyloxy; or optionally, when R₄ is twosubstituents attached to adjacent carbon atoms, the two substituentstogether form a single fused moiety; wherein the fused moiety isselected from the group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—,—(CH₂)₂₋₄O—, —O(CH₂)₁₋₃O— and —S—C(NH₂)═N—; R₅ is one to twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl,C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl andfluoro(C₁₋₆)alkanyloxy; A is absent or —(CH₂)_(m)—, wherein m is 2 or 3;Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—; X is O or S n is 0 or 1; Z is O, S,NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or N(phenyl); andenantiomers, diastereomers, tautomers, solvates, or pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1 wherein Gis —C(Z)NR₁R₂, phenyl, or a heterocycle selected from the groupconsisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, oxathiadiazolyl, imidazolinyl, tetrahydropyrimidinyl,thienyl, pyrazolyl, pyrimidinyl, triazinyl, furyl, isothiazolyl,isoxazolyl, oxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; whereinphenyl and the heterocycles of G are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl, carboxy(C₁₋₈)alkanyl,C₁₋₈alkanylcarbonylamino, halogen, hydroxy, cyano, oxo, thioxo, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, aminocarbonyl,aminothiocarbonyl, C₁₋₈alkanylaminocarbonyl,di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino.
 3. Thecompound according to claim 1 wherein G is —C(Z)NR₁R₂, phenyl, or aheterocycle selected from the group consisting of imidazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl,thienyl, pyrazolyl, pyrimidinyl, triazinyl, furyl, isothiazolyl,isoxazolyl, oxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; whereinphenyl and the heterocycles of G are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₄alkanyl, C₁₋₄alkanyloxy, hydroxy(C₁₋₄)alkanyl, carboxy(C₁₋₄)alkanyl,C₁₋₄alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, aminocarbonyl,aminothiocarbonyl, C₁₋₈alkanylaminocarbonyl, anddi(C₁₋₈alkanyl)aminocarbonyl.
 4. The compound according to claim 1wherein G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from thegroup consisting of imidazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,oxathiadiazolyl, thiophenyl, isothiazolyl, isoxazolyl, isoxadiazolyl,and pyridinyl; wherein phenyl and the heterocycles of G are optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy,hydroxy(C₁₋₄)alkanyl, C₁₋₄alkanylcarbonylamino, hydroxy, cyano, oxo,thioxo, and aminocarbonyl.
 5. The compound according to claim 1 whereinR₁ is a substituent selected from the group consisting of hydrogen andC₁₋₄alkanyl.
 6. The compound according to claim 1 wherein R₁ is selectedfrom the group consisting of hydrogen, methyl, ethyl, and propyl.
 7. Thecompound according to claim 1 wherein R₁ is selected from the groupconsisting of hydrogen, methyl, and ethyl.
 8. The compound according toclaim 1 wherein R₂ is selected from the group consisting of hydrogen;C₁₋₄alkanyl; phenyl; and C₃₋₆cycloalkanyl; provided that when Z is O orS, R₂ is other than hydrogen or unsubstituted C₁₋₄alkanyl; and, whereinC₁₋₄alkanyl is optionally substituted with one to three substituentsindependently selected from the group consisting of phenyl, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₄alkanyloxy, hydroxy, fluoro,chloro, cyano, aminocarbonyl, C₁₋₈alkanylaminocarbonyl,di(C₁₋₈alkanyl)aminocarbonyl, and phenoxy; wherein the phenyl andphenoxy substituents of C₁₋₄alkanyl are optionally further substitutedwith, and the phenyl and C₃₋₆cycloalkanyl substituents of R₂ areoptionally substituted with, one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, C₁₋₈alkanyloxy,trifluoromethyl, phenyl, fluoro, hydroxy, C₁₋₈alkanylthio,C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino; or R₁ and R₂ takentogether with the nitrogen to which they are attached form a 5-7membered cycloheteroalkyl optionally substituted with phenyl (whereinphenyl is optionally substituted with C₁₋₄alkanyloxy or hydroxy),C₁₋₄alkanyl, or hydroxy.
 9. The compound according to claim 1 wherein R₂is selected from the group consisting of C₁₋₄alkanyl, phenyl, andC₃₋₆cycloalkanyl; provided that when Z is O or S, R₂ is other thanunsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of phenyl, C₁₋₄alkanyloxy, hydroxy, fluoro,aminocarbonyl, C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl,and phenoxy; wherein the phenyl and phenoxy substituents of C₁₋₄alkanylare optionally further substituted with, and the phenyl of R₂ isoptionally substituted with, one to three substituents independentlyselected from the group consisting of C₁₋₆alkanyl, C₁₋₆alkanyloxy,fluoro, hydroxy, and C₁₋₆alkanylthio; or R₁ and R₂ taken together withthe nitrogen to which they are attached form a pyrrolidinyl orpiperidinyl ring wherein said pyrrolidinyl or piperidinyl is optionallysubstituted with a substituent selected from the group consisting ofC₁₋₄alkanyl and hydroxy.
 10. The compound according to claim 1 whereinR₂ is selected from the group consisting of C₁₋₄alkanyl and phenyl;provided that when Z is O or S, R₂ is other than unsubstitutedC₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is optionally substituted with oneto three substituents independently selected from the group consistingof phenyl, C₁₋₄alkanyloxy, hydroxy, fluoro, and phenoxy; wherein thephenyl and phenoxy substituents of C₁₋₄alkanyl are optionally furthersubstituted with, and the phenyl of R₂ is optionally substituted with,one to three substituents independently selected from the groupconsisting of C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, and hydroxy; or R₁and R₂taken together with the nitrogen to which they are attached form apyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl orpiperidinyl is optionally substituted with a substituent selected fromthe group consisting of C₁₋₃alkanyl and hydroxy.
 11. The compoundaccording to claim 1 wherein R₃ is selected from the group consisting ofhydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein heteroaryl isselected from the group consisting of benzo[1,3]dioxolyl, imidazolyl,furanyl, pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₆alkanyloxy and hydroxy; or optionally, whenphenyl and heteroaryl are optionally substituted with two substituentsattached to adjacent carbon atoms, the two substituents together form asingle fused moiety; wherein the moiety is selected from —O(CH₂)₁₋₃O—.12. The compound according to claim 1 wherein R₃ is selected from thegroup consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl,hydroxyethyl, methylthioethyl, methoxyethyl, thioformyl,phenyliminomethyl, phenethyl, and heteroaryl(C₁₋₈)alkanyl wherein theheteroaryl is selected from the group consisting of benzo[1,3]dioxolyl,imidazolyl, furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl,quinolinyl, isoquinolinyl, tetrazolyl; wherein the phenyl in anyphenyl-containing substituent is optionally substituted with onehydroxyl group.
 13. The compound according to claim 1 wherein R₃ ishydrogen, methyl, allyl, or heteroarylmethyl wherein heteroaryl isselected from the group consisting of benzo[1,3]dioxolyl, imidazolyl,furanyl, pyridinyl, and thienyl.
 14. The compound according to claim 1wherein R₄ is one to three substituents independently selected from thegroup consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,aminocarbonyl, aminothiocarbonyl, hydroxyamidino, formylamino,C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen, hydroxy,C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl,indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, and thienyl.
 15. Thecompound according to claim 1 wherein R₄ is one to two substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thienyl, hydroxy, and aminocarbonyl.
 16. The compound according to claim1 wherein R₄ is one to two substituents independently selected from thegroup consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy.
 17. Thecompound according to claim 1 wherein R₅ is one to two substituentsindependently selected from the group consisting of hydrogen andhalogen.
 18. The compound according to claim 1 wherein R₅ is hydrogen.19. The compound according to claim 1 wherein A is absent or —(CH₂)₂—.20. The compound according to claim 1 wherein A is —(CH₂)₂—.
 21. Thecompound according to claim 1 wherein X is O or S.
 22. The compoundaccording to claim 1 wherein n is
 0. 23. The compound according to claim1 wherein Z is O, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), orN(phenyl).
 24. The compound according to claim 1 wherein Z is O, NH, orN(OH).
 25. The compound according to claim 1 wherein Z is O or NH.
 26. Acompound of Formula (I):

wherein: G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from thegroup consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, oxathiadiazolyl, imidazolinyl, tetrahydropyrimidinyl,thienyl, pyrazolyl, pyrimidinyl, triazinyl, furyl, isothiazolyl,isoxazolyl, oxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl; whereinphenyl and the heterocycles of G are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl, carboxy(C₁₋₈)alkanyl,C₁₋₈alkanylcarbonylamino, halogen, hydroxy, cyano, oxo, thioxo, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, aminocarbonyl,aminothiocarbonyl, C₁₋₈alkanylaminocarbonyl,di(C₁₋₈alkanyl)aminocarbonyl, and C₁₋₆alkanyloxycarbonylamino; R₁ ishydrogen or C₁₋₄alkanyl; R₂ is selected from the group consisting ofhydrogen; C₁₋₄alkanyl; phenyl; and C₃₋₆cycloalkanyl; provided that whenZ is O or S, R₂ is other than hydrogen or unsubstituted C₁₋₄alkanyl;and, wherein C₁₋₄alkanyl is optionally substituted with one to threesubstituents independently selected from the group consisting of phenyl,amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₄alkanyloxy, hydroxy,fluoro, chloro, cyano, aminocarbonyl, C₁₋₈alkanylaminocarbonyl,di(C₁₋₈alkanyl)aminocarbonyl, and phenoxy; wherein the phenyl andphenoxy substituents of C₁₋₄alkanyl are optionally further substitutedwith, and the phenyl and C₃₋₆cycloalkanyl substituents of R₂ areoptionally substituted with, one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, C₁₋₈alkanyloxy,trifluoromethyl, phenyl, fluoro, hydroxy, C₁₋₈alkanylthio,C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino; or R₁ and R₂ takentogether with the nitrogen to which they are attached form a 5-7membered cycloheteroalkyl optionally substituted with phenyl (whereinphenyl is optionally substituted with C₁₋₄alkanyloxy or hydroxy),C₁₋₄alkanyl, or hydroxy; R₃ is selected from the group consisting ofhydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein heteroaryl isselected from the group consisting of benzo[1,3]dioxolyl, imidazolyl,furanyl, pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₆alkanyloxy and hydroxy; or optionally, whenphenyl and heteroaryl are optionally substituted with two substituentsattached to adjacent carbon atoms, the two substituents together form asingle fused moiety; wherein the moiety is selected from —O(CH₂)₁₋₃O—;R₄ is one to three substituents independently selected from the groupconsisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, aminocarbonyl,aminothiocarbonyl, hydroxyamidino, formylamino,C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen, hydroxy,C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl,indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, and thienyl; R₅ isone to two substituents independently selected from the group consistingof hydrogen and halogen; A is absent or —(CH₂)₂—; Y is O, S, CH₂O orOCH₂; Z is O, NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or N(phenyl);and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 27. A compound of Formula(I):

wherein: G is —C(Z)NR₁R₂, phenyl, or a heterocycle selected from thegroup consisting of imidazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl, pyrimidinyl,triazinyl, furyl, isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl,quinolinyl, and pyridinyl; wherein phenyl and the heterocycles of G areoptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy,hydroxy(C₁₋₄)alkanyl, carboxy(C₁₋₄)alkanyl, C₁₋₄alkanylcarbonylamino,hydroxy, cyano, oxo, thioxo, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio, aminocarbonyl, aminothiocarbonyl,C₁₋₈alkanylaminocarbonyl, and di(C₁₋₈alkanyl)aminocarbonyl; R₁ isselected from the group consisting of hydrogen, methyl, ethyl, andpropyl; R₂ is selected from the group consisting of C₁₋₄alkanyl, phenyl,and C₃₋₆cycloalkanyl; provided that when Z is O or S, R₂ is other thanunsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanyl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of phenyl, C₁₋₄alkanyloxy, hydroxy, fluoro,aminocarbonyl, C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl,and phenoxy; wherein the phenyl and phenoxy substituents of C₁₋₄alkanylare optionally further substituted with, and the phenyl of R₂ isoptionally substituted with, one to three substituents independentlyselected from the group consisting of C₁₋₆alkanyl, C₁₋₆alkanyloxy,fluoro, hydroxy, and C₁₋₆alkanylthio; or R₁ and R₂ taken together withthe nitrogen to which they are attached form pyrrolidinyl or piperidinylring wherein said pyrrolidinyl or piperidinyl is optionally substitutedwith a substituent selected from the group consisting of C₁₋₃alkanyl andhydroxy; R₃ is selected from the group consisting of hydrogen, methyl,allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, andheteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from thegroup consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl,thienyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl;wherein the phenyl in any phenyl-containing substituent is optionallysubstituted with one hydroxyl group; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thienyl, hydroxy, and aminocarbonyl; R₅ is hydrogen; A is —(CH₂)₂—; Y isO or S; Z is O, NH, or N(OH); and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 28. Thecompound according to claim 27 wherein G is —C(Z)NR₁R₂, phenyl, or aheterocycle selected from the group consisting of imidazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, thienyl,isothiazolyl, isoxazolyl, isoxadiazolyl, quinolinyl, and pyridinyl;wherein phenyl and the heterocycles of G are optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₄alkanyl, C₁₋₄alkanyloxy, hydroxy(C₁₋₄)alkanyl,C₁₋₄alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, andaminocarbonyl.
 29. The compound according to claim 27 wherein G is—C(Z)NR₁R₂, 2-methylcarbonylaminophenyl, 2-aminocarbonyl-phenyl,1H-tetrazol-5-yl, 2-methyl-tetrazol-5-yl,4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, orpyridin-3-yl.
 30. The compound according to claim 27 wherein R₂ isselected from the group consisting of C₁₋₄alkanyl and phenyl; providedthat when Z is O or S, R₂ is other than unsubstituted C₁₋₄alkanyl; and,wherein C₁₋₄alkanyl is optionally substituted with one to threesubstituents independently selected from the group consisting of phenyl,C₁₋₄alkanyloxy, hydroxy, fluoro, and phenoxy; wherein the phenyl andphenoxy substituents of C₁₋₄alkanyl are optionally further substitutedwith, and the phenyl of R₂ is optionally substituted with, one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, and hydroxy; or R₁ and R₂ takentogether with the nitrogen to which they are attached form apyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl orpiperidinyl is optionally substituted with a substituent selected fromC₁₋₃alkanyl or hydroxy; and R₃ is a substituent selected from the groupconsisting of benzo[1,3]dioxol-5-ylmethyl, carbamimidoyl,1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl,2-hydroxyphenyl-methyl, hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl,2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl,phenethyl, pyridin-2-yl methyl, and thiophen-2-yl methyl.
 31. A compoundof Formula (I):

wherein: G is selected from —C(Z)NR₁R₂, 2-methylcarbonylaminophenyl,2-aminocarbonyl-phenyl, 1H-tetrazol-5-yl, 2-methyl-tetrazol-5-yl,4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, orpyridin-3-yl; R₁ is hydrogen, methyl, or ethyl; R₂ is selected from thegroup consisting of C₁₋₄alkanyl and phenyl; provided that when Z is O orS, R₂ is other than unsubstituted C₁₋₄alkanyl; and, wherein C₁₋₄alkanylis optionally substituted with one to three substituents independentlyselected from the group consisting of phenyl, C₁₋₄alkanyloxy, hydroxy,fluoro, and phenoxy; wherein the phenyl and phenoxy substituents ofC₁₋₄alkanyl are optionally further substituted with, and the phenyl ofR₂ is optionally substituted with, one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl,C₁₋₆alkanyloxy, fluoro, and hydroxy; or R₁ and R₂ taken together withthe nitrogen to which they are attached form a pyrrolidinyl orpiperidinyl ring wherein said pyrrolidinyl or piperidinyl is optionallysubstituted with a substituent selected from C₁₋₃alkanyl or hydroxy; R₃is selected from the group consisting of hydrogen, methyl, allyl,2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl, methoxyethyl,thioformyl, phenyliminomethyl, phenethyl, and heteroaryl(C₁₋₈)alkanylwherein the heteroaryl is selected from the group consisting ofbenzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl; whereinthe phenyl in any phenyl-containing substituent is optionallysubstituted with one hydroxyl group; R₄ is one to three substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thienyl, hydroxy, and aminocarbonyl; R₅ is hydrogen; A is —(CH₂)₂—; Y isO or S; Z is O or NH; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 32. Thecompound according to claim 31 wherein R₂ is a substituent selected fromthe group consisting of C₁₋₄alkanyl and phenyl; provided that when Z isO or S, R₂ is other than unsubstituted C₁₋₄alkanyl; and, whereinC₁₋₄alkanyl is optionally substituted with one to three substituentsindependently selected from the group consisting of phenyl,C₁₋₄alkanyloxy, hydroxy, and 2,6-dimethyl-phenoxy; one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl, C₁₋₆alkanyloxy, fluoro, and hydroxy; or R₁ and R₂takentogether with the nitrogen to which they are attached form apyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl orpiperidinyl is optionally substituted with a substituent selected fromC₁₋₃alkanyl or hydroxy.
 33. The compound according to claim 31 whereinR₃ is a substituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl,allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, and thiophen-2-ylmethyl; and R₄ is one to two substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thienyl, and hydroxy.
 34. The compound according to claim 31 wherein R₃is a substituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl methyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxyethyl, methoxyethyl, allyl, furan-3-yl methyl, H, Me,methylthioethyl, and phenethyl; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy.
 35. The compound according to claim 31 whereinR₃ is a substituent selected from the group consisting of H,benzo[1,3]dioxol-5-ylmethyl, 1-H-imidazol-4-yl methyl, furan-3-ylmethyl,pyridin-2-ylmethyl, and phenyliminomethyl; and R₄ is a substituentindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy.
 36. A compound of Formula (I):

selected from the group consisting of: a compound of Formula (I) whereinG is 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅is H; and Y is O; a compoundof Formula (I) wherein G is 2-methylcarbonylaminophenyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-hydroxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃is H; R₄is H; R₅is H; and Y is O; acompound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H; R₄ isH; R₅is H; and Y is O; a compound of Formula (I) wherein G is[1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃is H; R₄is H; R₅is H; and Y is O; acompound of Formula (I) wherein G isN-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is N-(1(S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃is H; R₄is H; R₅isH; and Y is O; a compound of Formula (I) wherein G is2-methyl-tetrazol-5-yl; R₃ is H; R₄is H; R₅is H; and Y is O; a compoundof Formula (I) wherein G is N-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 2-aminocarbonyl-phenyl; R₃ is H; R₄is H; R₅is H; and Y is O; acompound of Formula (I) wherein G is 2-phenylethyl-aminocarbonyl; R₃isH; R₄is H; R₅is H; and Y is O; a compound of Formula (I) wherein G is3-methylcarbonylamino-phenyl; R₃is H; R₄is H; R₅is H; and Y is O; acompound of Formula (I) wherein G is 1-methyl-tetrazol-5-yl; R₃ is H;R₄is H; R₅is H; and Y is O; a compound of Formula (I) wherein G isN-cyclohexyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is 3-hydroxymethyl-phenyl; R₃ isH; R₄is H; R₅is H; and Y is O; a compound of Formula (I) wherein G isN-hydroxyamidino; R₃ is H; R₄ is H; R₅is H; and Y is O; a compound ofFormula (I) wherein G is 2-aminophenyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is 5-ethyl-1H-imidazol-2-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is N-(1(R)-hydroxymethyl-2-phenyl-eth-1-yl)-aminocarbonyl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is N,N-diisobutylamidino; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is4-methylcarbonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-(1S-methoxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methoxypyridin-5-yl; R₃ is H; R₄is H; R₅is H; and Y is O; a compoundof Formula (I) wherein G is 4,5-dihydro-1H-imidazol-2-yl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(4-phenyl)-cyclohexyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is3-methyl-4H-[1,2,4]triazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 5-methyl-[1,2,4]oxadiazol-4-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is N-(1 (S)-hydroxymethyl-1-methoxycarbonyl)aminocarbonyl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is3-hydroxy-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is isopropylamidino; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G isphenylmethylaminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G is 1,4,5,6-tetrahydropyrimidin-2-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 4-aminophenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is C-piperidin-1-yl-methyleneamine; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methoxyphenyl; R₃ is H; R₄ is H; R₅is H; and Y is O; a compound ofFormula (I) wherein G is cyclopentylaminocarbonyl; R₃ is H; R₄ is H; R₅is H; and Y is O; a compound of Formula (I) wherein G is 3-methylphenyl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is phenylaminocarbonyl; R₃ is H; R₄is H; R₅is H; and Y is O; acompound of Formula (I) wherein G is N,N-bis(2,2,2-trifluoro-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is isobutylamidino; R₃ is H;R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isC-morpholin-4-yl-methyleneamine; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 3-fluorophenyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-benzyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 4-methanesulfonyl-phenyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is4-fluorophenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is thiophen-3-yl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G isN-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is3-methoxyphenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is phenylmethylaminocarbonyl; R₃ isethoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I)wherein G is phenylaminocarbonyl; R₃ is ethoxycarbonyl; R₄ is H; R₅ isH; and Y is O; a compound of Formula (I) wherein G iscyclopentylaminocarbonyl; R₃ is ethoxycarbonyl; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G isN-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ isethoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I)wherein G is N-[(4-trifluoromethyl)-cyclohexyl]-aminocarbonyl; R₃ is H;R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is3-methanesulfonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-2,2,2,-trifluoroethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is3-[(3-methoxy)phenyl]piperidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G isN-4-fluorophenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G isN-(1(R)-hydroxymethyl-3-methyl-but-1-yl)-aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is(3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is(3(S)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is 5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis N-(2-hydroxy-ethyl)-N-methyl-aminocarbonyl; R₃ is ethoxycarbonyl; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃is H; R₄ is 5-methoxy; R₅ is H; and Y is O; a compound of Formula (I)wherein G is phenylthio; R₃ is H; R₄ is H; R₅ is H; and Y is S; acompound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ is5-hydroxy; R₅ is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 4H-[1,2,4]-oxadiazol-5-oxo-3-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (Ib) wherein G is methoxycarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-hydroxy-1,1-dimethyl-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ isH; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 1 H-tetrazol-5-yl; R₃ is H; R₄ isH; R₅is H; and Y is S; a compound of Formula (I) wherein G is1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ isH; and Y is O; a compound of Formula (I) wherein G is fur-3-yl; R₃ is H;R₄ is 5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) whereinG is thien-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O; acompound of Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methylcarbonylamino-phenyl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Yis O; a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄is 5-hydroxy; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis N-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is 1-methyl-pyrazol-3-yl; R₃is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis pyridin-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is 2-methylcarbonylamino-phenyl; R₃ is H; R₄ is H;R₅ is H; and Y is S; a compound of Formula (I) wherein G ispyridin-3-yl; R₃ is methyl; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is pyridin-3-yl; R₃ is 1H-imidazol-2-ylmethyl; R₄is H; R₅ is H; and Y is S; a compound of Formula (I) wherein G ispyridin-3-yl; R₃ is fur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S; acompound of Formula (I) wherein G is pyridin-3-yl; R₃ ispyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound of Formula(I) wherein G is 2-methylcarbonylamino-phenyl; R₃ is methyl; R₄ is H; R₅is H; and Y is S; a compound of Formula (I) wherein G is2-methylcarbonylamino-phenyl; R₃ is 1H-imidazol-2-ylmethyl; R₄ is H; R₅is H; and Y is S; a compound of Formula (I) wherein G is2-methylcarbonylamino-phenyl; R₃ is fur-3-ylmethyl; R₄ is H; R₅ is H;and Y is S; a compound of Formula (I) wherein G is2-methylcarbonylamino-phenyl; R₃ is pyridin-2-ylmethyl; R₄ is H; R₅ isH; and Y is S; a compound of Formula (I) wherein G isN-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is t-butoxycarbonyl; R₄ is H; R₅is H; and Y is O; a compound of Formula (I) wherein G isN-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G isN-(2-hydroxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is N,N-diethylamidino;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is N,N-diethylamidino; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G is(3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ istrifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is pyridin-3-yl; R₃ is trifluoromethylcarbonyl; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methylcarbonylaminophenyl; R₃ is trifluoromethylcarbonyl; R₄ is H; R₅is H; and Y is O; a compound of Formula (I) wherein G is2-methylcarbonylaminophenyl; R₃ is trifluoromethylcarbonyl; R₄ is H; R₅is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; andY is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;and Y is O; and a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H; andY is O.
 37. A compound of Formula (I):

selected from the group consisting of: a compound of Formula (I) whereinG is 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is 2-methylcarbonylaminophenyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is[1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G isN-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G isN-(1(S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methyl-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 2-phenylethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl; R₃is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 1-methyl-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-cyclohexyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is 3-hydroxymethyl-phenyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-hydroxyamidino; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is 2-aminophenyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is 5-ethyl-1H-imidazol-2-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is N-(1(R)-hydroxymethyl-2-phenyl-eth-1-yl)-aminocarbonyl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is N,N-diisobutylamidino; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is4-methylcarbonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-(1S-methoxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methoxypyridin-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is 4,5-dihydro-1H-imidazol-2-yl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(4-phenyl)-cyclohexyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is3-methyl-4H-[1,2,4]triazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G isN-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ isethoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I)wherein G is 3-methanesulfonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G isN-2,2,2,-trifluoroethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is3-[(3-methoxy)phenyl]piperidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G isN-4-fluorophenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G isN-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is(3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is(3(S)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is 5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅is H; and Y is O; a compound ofFormula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ is 5-methoxy; R₅is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 4H-[1,2,4]-oxadiazol-5-oxo-3-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G isN-(2-hydroxy-1,1-dimethyl-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ isH; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ isH; R₅ is H; and Y is S; a compound of Formula (I) wherein G is1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is quinolin-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ isH; and Y is O; a compound of Formula (I) wherein G is fur-3-yl; R₃ is H;R₄ is 5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) whereinG is thien-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O; acompound of Formula (I) wherein G is pyridin-4-yl; R₃ is H; R₄ is5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methylcarbonylamino-phenyl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Yis O; a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄is 5-hydroxy; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 1-methyl-pyrazol-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl; R₃ isH; R₄ is H; R₅ is H; and Y is S; a compound of Formula (I) wherein G ispyridin-3-yl; R₃ is methyl; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is pyridin-3-yl; R₃ is 1 H-imidazol-2-ylmethyl; R₄is H; R₅ is H; and Y is S; a compound of Formula (I) wherein G ispyridin-3-yl; R₃ is fur-3-ylmethyl; R₄is H; R₅is H; and Y is S; acompound of Formula (I) wherein G is pyridin-3-yl; R₃ ispyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound of Formula(I) wherein G is 2-methylcarbonylamino-phenyl; R₃ is1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is 2-methylcarbonylamino-phenyl; R₃ isfur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound of Formula (I)wherein G is 2-methylcarbonylamino-phenyl; R₃ is pyridin-2-ylmethyl; R₄is H; R₅ is H; and Y is S; a compound of Formula (I) wherein G isN-(2-hydroxy-ethyl)-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H;R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is(3(R)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; andY is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;and Y is O; and a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H; andY is O.
 38. A compound of Formula (I):

selected from the group consisting of: a compound of Formula (I) whereinG is 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is 2-methylcarbonylaminophenyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is[1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G isN-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G isN-(1(S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methyl-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 2-phenylethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl; R₃is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 1-methyl-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-cyclohexyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is 3-hydroxymethyl-phenyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-hydroxyamidino; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is 2-aminophenyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is 5-ethyl-1H-imidazol-2-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is N-(1(R)-hydroxymethyl-2-phenyl-eth-1-yl)-aminocarbonyl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ isethoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I)wherein G is N-2,2,2,-trifluoroethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅is H; and Y is O; a compound of Formula (I) wherein G is3-[(3-methoxy)phenyl]piperidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G isN-4-fluorophenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G isN-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is(3(S)-hydroxy)pyrrolidin-1-ylcarbonyl; R₃ is H; R₄ is H; R₅ is H; and Yis O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is 5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ is 5-methoxy;R₅ is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 4H-[1,2,4]-oxadiazol-5-oxo-3-yl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ isH; R₅ is H; and Y is S; a compound of Formula (I) wherein G is1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅is H; and Y is S; a compound ofFormula (I) wherein G is fur-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;and Y is O; a compound of Formula (I) wherein G is2-methylcarbonylamino-phenyl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Yis O; a compound of Formula (I) wherein G is quinolin-3-yl; R₃ is H; R₄is 5-hydroxy; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 2-methylcarbonylamino-phenyl; R₃ is H; R₄ is H; R₅ is H; and Y is S;a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is1H-imidazol-2-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is pyridin-3-yl; R₃ is fur-3-ylmethyl; R₄ is H; R₅is H; and Y is S; a compound of Formula (I) wherein G is pyridin-3-yl;R₃ is pyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is 2-methylcarbonylamino-phenyl; R₃ isfur-3-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound of Formula (I)wherein G is 2-methylcarbonylamino-phenyl; R₃ is pyridin-2-ylmethyl; R₄is H; R₅ is H; and Y is S; a compound of Formula (I) wherein G isN,N-diethylamidino; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (I) wherein G is 4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;and Y is O; and a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H; andY is O.
 39. A compound of Formula (I):

selected from the group consisting of: a compound of Formula (I) whereinG is 1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is 2-methylcarbonylaminophenyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is pyrrolidin-1-ylcarbonyl; R₃ isH; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-(2-methoxy-ethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is N,N-diethylamidino; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G is[1,2,3,5]oxathiadiazol-2-oxo-4-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G isN-(3-fluorophenyl)-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is pyridin-3-yl; R₃ is H; R₄is H; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]aminocarbonyl; R₃ is H; R₄ isH; R₅ is H; and Y is O; a compound of Formula (I) wherein G isN-phenyl-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G isN-(1(S)-hydroxymethyl-2-phenyl-eth-1-yl)aminocarbonyl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is2-methyl-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (I) wherein G isN-(2-phenylethyl)-N-methyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; andY is O; a compound of Formula (I) wherein G is 2-aminocarbonyl-phenyl;R₃ is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) whereinG is 2-phenylethyl-aminocarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 3-methylcarbonylamino-phenyl; R₃is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis N-(2-dimethylamino-eth-1-yl)-N-methyl-aminocarbonyl; R₃ isethoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I)wherein G is N-(dimethylaminocarbonylmethyl)-N-methyl-aminocarbonyl; R₃is H; R₄ is H; R₅is H; and Y is O; a compound of Formula (I) wherein Gis pyridin-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O; acompound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ is H;R₅ is H; and Y is O; a compound of Formula (I) wherein G is1H-tetrazol-5-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; and Y is O; acompound of Formula (I) wherein G is 4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃is H; R₄ is H; R₅ is H; and Y is O; a compound of Formula (I) wherein Gis 4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]thiadiazol-5-oxo-3-yl; R₃ is H; R₄ is H; R₅ is H; and Y is O;a compound of Formula (I) wherein G is 1H-tetrazol-5-yl; R₃ is H; R₄ isH; R₅ is H; and Y is S; a compound of Formula (I) wherein G is1H-tetrazol-5-yl; R₃ is H; R₄ is H; R₅ is H; and Y is S; a compound ofFormula (I) wherein G is 2-methylcarbonylamino-phenyl; R₃ is H; R₄ is5-methoxy; R₅ is H; and Y is O; a compound of Formula (I) wherein G isquinolin-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H; and Y is O; a compoundof Formula (I) wherein G is 2-methylcarbonylamino-phenyl; R₃ ispyridin-2-ylmethyl; R₄ is H; R₅ is H; and Y is S; a compound of Formula(I) wherein G is N,N-diethylamidino; R₃ is H; R₄ is H; R₅ is H; and Y isO; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H; andY is O; a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-thioxo-3-yl; R₃ is H; R₄ is 5-methoxy; R₅ is H;and Y is O; and a compound of Formula (I) wherein G is4H-[1,2,4]-oxadiazol-5-oxo-3-yl; R₃ is H; R₄ is 5-hydroxy; R₅ is H; andY is O.
 40. A compound of Formula (Ib):

selected from the group consisting of: a compound of Formula (Ib)wherein G is carboxy; R₃ is H; R₄ is H; R₅ is H; and Y is O; a compoundof Formula (Ib) wherein G is methoxycarbonyl; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (Ib) wherein G is methoxycarbonyl; R₃is ethoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula(Ib) wherein G is methoxycarbonyl; R₃ is H; R₄ is H; R₅ is H; and Y isS; a compound of Formula (Ib) wherein G is cyano; R₃ is H; R₄ is H; R₅is H; and Y is O; a compound of Formula (Ib) wherein G ismethoxycarbonyl; R₃ is H; R₄ is 6-methoxycarbonyl; R₅ is H; and Y is O;a compound of Formula (Ib) wherein G is bromo; R₃ is H; R₄ is 5-methoxy;R₅ is H; and Y is O; a compound of Formula (Ib) wherein G is bromo; R₃is H; R₄ is H; R₅ is H; and Y is S; a compound of Formula (Ib) wherein Gis cyano; R₃ is H; R₄ is H; R₅ is H; and Y is S; a compound of Formula(Ib) wherein G is cyano; R₃ is H; R₄ is H; R₅ is H; and Y is O; acompound of Formula (Ib) wherein G is cyano; R₃ is H; R₄ is H; R₅ is H;and Y is O; a compound of Formula (Ib) wherein G is cyano; R₃ istrifluoromethylcarbonyl; R₄ is H; R₅ is H; and Y is O; a compound ofFormula (Ib) wherein G is cyano; R₃ is trifluoromethylcarbonyl; R₄ is H;R₅ is H; and Y is O; a compound of Formula (Ib) wherein G is carboxy; R₃is t-Butoxycarbonyl; R₄ is H; R₅ is H; and Y is O; a compound of Formula(Ib) wherein G is carboxy; R₃ is H; R₄ is H; R₅ is H; and Y is O; and acompound of Formula (Ib) wherein G is carboxy; R₃ is H; R₄ is H; R₅ isH; and Y is O.
 41. A composition comprising the dextrorotatoryenantiomer of a compound of of formula (I) wherein said composition issubstantially free from the levorotatory isomer of said compound.
 42. Acomposition comprising the levororotatory enantiomer of a compound offormula (I) wherein said composition is substantially free from thedextrorotatory isomer of said compound.
 43. A pharmaceutical compositioncomprising a compound, salt or solvate according to any of claims 1admixed with a pharmaceutically acceptable carrier, excipient ordiluent.
 44. A veterinary composition comprising a compound, salt orsolvate according to claim 1 admixed with a veterinarily acceptablecarrier, excipient or diluent.
 45. A method of treating or preventing adisease or condition in a mammal which disease or condition is affectedby the modulation of delta opioid receptors, which method comprisesadministering to a mammal in need of such treatment or prevention atherapeutically effective amount of a compound, salt or solvate ofclaim
 1. 46. The method of claim 45 wherein said therapeuticallyeffective amount comprises a dose range of from about 0.1 mg to about1,000 mg.
 47. The method of claim 45 wherein said therapeuticallyeffective amount comprises a dose range of from about 50 mg to about1000 mg.
 48. The method of claim 45 wherein said therapeuticallyeffective amount comprises a dose range of from about 100 mg to about1000 mg.
 49. A method for preventing or treating mild to severe paincomprising the step of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound, salt orsolvate of claim
 1. 50. The method of claim 49 wherein the pain isselected from the group consisting of inflammatory pain, centrallymediated pain, peripherally mediated pain, visceral pain, structuralrelated pain, cancer/pain, soft tissue injury related pain, progressivedisease related pain, neuropathic pain and acute pain from acute injury,acute pain from trauma, acute pain from surgery, chronic pain fromheadache, chronic pain from neuropathic conditions, chronic pain frompost-stroke conditions and chronic pain from migraine.
 51. The method ofclaim 49 wherein the pain is caused by a disease or condition selectedfrom the group consisting of osteoarthritis, rheumatoid arthritis,fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite,spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminalneuralgia, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory boweldisease, irritable bowel syndrome, sinus headache, tension headache,labor, childbirth, menstrual cramps, and cancer.
 52. A method fortreating or preventing a disease or condition selected from the groupconsisting of depression, Parkinson's disease, drug abuse, alcoholabuse, gastritis, urinary incontinence, premature ejaculation, diarrhea,cardiovascular disease, and respiratory diseases, said method comprisingthe step of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate ofclaim
 1. 53. The method of claim 49 wherein said therapeuticallyeffective amount comprises a dose range of from about 0.1 mg to about1,000 mg.
 54. The method of claim 49 wherein said therapeuticallyeffective amount comprises a dose range of from about 50 mg to about1000 mg.
 55. The method of claim 49 wherein said therapeuticallyeffective amount comprises a dose range of from about 100 mg to about1000 mg.
 56. A kit comprising in one or more containers an amount of thecomposition of claim 1 effective to treat or prevent mild to severepain.
 57. A pharmaceutical composition comprising a compound, salt orsolvate according to claim 26 admixed with a pharmaceutically acceptablecarrier, excipient or diluent.
 58. A veterinary composition comprising acompound, salt or solvate according to claim 26 admixed with aveterinarily acceptable carrier, excipient or diluent.
 59. A method forpreventing or treating mild to severe pain, said method comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate of claim26.
 60. The method of claim 59 wherein the pain is selected from thegroup consisting of inflammatory pain, centrally mediated pain,peripherally mediated pain, visceral pain, structural related pain,cancer pain, soft tissue injury related pain, progressive diseaserelated pain, neuropathic pain and acute pain from acute injury, acutepain from trauma, acute pain from surgery, chronic pain from headache,chronic pain from neuropathic conditions, chronic pain from post-strokeconditions and chronic pain from migraine.
 61. The method of claim 59wherein the pain is caused by a disease or condition selected from thegroup consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia,migraine, headache, toothache, burn, sunburn, snake bite, spider bite,insect sting, neurogenic bladder, benign prostatic hypertrophy,interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia,sciatic neuritis, mandibular joint neuralgia, peripheral neuritis,polyneuritis, stump pain, phantom limb pain, post-operative ileus,cholecystitis, postmastectomy pain syndrome, oral neuropathic pain,Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,meralgia paresthetica, burning-mouth syndrome, post-herpetic neuralgia,trigeminal neuralgia, cluster headache, migraine headache, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,postherpetic neuralgia, trigeminal neuralgia, optic neuritis,postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault'sneuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia,idiopathic neuralgia, intercostals neuralgia, mammary neuralgia,Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, redneuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbitalneuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowelsyndrome, sinus headache, tension headache, labor, childbirth, menstrualcramps, and cancer.
 62. A method for treating or preventing a disease orcondition selected from the group consisting of depression, Parkinson'sdisease, drug abuse, alcohol abuse, gastritis, urinary incontinence,premature ejaculation, diarrhea, cancer/pain, cardiovascular disease,and respiratory diseases, said method comprising the step ofadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound, salt or solvate of claim
 26. 63. Themethod of claim 59 wherein said therapeutically effective amountcomprises a dose range of from about 0.1 mg to about 1,000 mg.
 64. Themethod of claim 59 wherein said therapeutically effective amountcomprises a dose range of from about 50 mg to about 1000 mg.
 65. Themethod of claim 59 wherein said therapeutically effective amountcomprises a dose range of from about 100 mg to about 1000 mg.
 66. A kitcomprising in one or more containers an amount of the composition ofclaim 26 effective to treat or prevent mild to severe pain.
 67. Apharmaceutical composition comprising a compound, salt or solvateaccording to claim 31 admixed with a pharmaceutically acceptablecarrier, excipient or diluent.
 68. A veterinary composition comprising acompound, salt or solvate according to claim 31 admixed with aveterinarily acceptable carrier, excipient or diluent.
 69. A method forpreventing or treating mild to severe pain, said method comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate of claim31.
 70. The method of claim 69 wherein the pain is selected from thegroup consisting of inflammatory pain, centrally mediated pain,peripherally mediated pain, visceral pain, structural related pain,cancer pain, soft tissue injury related pain, progressive diseaserelated pain, neuropathic pain and acute pain from acute injury, acutepain from trauma, acute pain from surgery, chronic pain from headache,chronic pain from neuropathic conditions, chronic pain from post-strokeconditions and chronic pain from migraine.
 71. The method of claim 69wherein the pain is caused by a disease or condition selected from thegroup consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia,migraine, headache, toothache, burn, sunburn, snake bite, spider bite,insect sting, neurogenic bladder, benign prostatic hypertrophy,interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia,sciatic neuritis, mandibular joint neuralgia, peripheral neuritis,polyneuritis, stump pain, phantom limb pain, post-operative ileus,cholecystitis, postmastectomy pain syndrome, oral neuropathic pain,Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,meralgia paresthetica, burning-mouth syndrome, post-herpetic neuralgia,trigeminal neuralgia, cluster headache, migraine headache, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,postherpetic neuralgia, trigeminal neuralgia, optic neuritis,postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault'sneuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia,idiopathic neuralgia, intercostals neuralgia, mammary neuralgia,Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, redneuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbitalneuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowelsyndrome, sinus headache, tension headache, labor, childbirth, menstrualcramps, and cancer.
 72. A method for treating or preventing a disease orcondition selected from the group consisting of depression, Parkinson'sdisease, drug abuse, alcohol abuse, gastritis, urinary incontinence,premature ejaculation, diarrhea, cardiovascular disease, and respiratorydiseases, said method comprising the step of administering to a mammalin need of such treatment a therapeutically effective amount of acompound, salt or solvate of claim
 31. 73. The method of claim 69wherein said therapeutically effective amount comprises a dose range offrom about 0.1 mg to about 1,000 mg.
 74. The method of claim 69 whereinsaid therapeutically effective amount comprises a dose range of fromabout 50 mg to about 1000 mg.
 75. The method of claim 69 wherein saidtherapeutically effective amount comprises a dose range of from about100 mg to about 1000 mg.
 76. A kit comprising in one or more containersan amount of the composition of claim 31 effective to treat or preventmild to severe pain.
 77. A pharmaceutical composition comprising acompound, salt or solvate according to claim 36 admixed with apharmaceutically acceptable carrier, excipient or diluent.
 78. Aveterinary composition comprising a compound, salt or solvate accordingto claim 36 admixed with a veterinarily acceptable carrier, excipient ordiluent.
 79. A method for preventing or treating mild to severe pain,said method comprising the step of administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound, salt orsolvate of claim
 36. 80. The method of claim 79 wherein the pain isselected from the group consisting of inflammatory pain, centrallymediated pain, peripherally mediated pain, visceral pain, structuralrelated pain, cancer pain, soft tissue injury related pain, progressivedisease related pain, neuropathic pain and acute pain from acute injury,acute pain from trauma, acute pain from surgery, chronic pain fromheadache, chronic pain from neuropathic conditions, chronic pain frompost-stroke conditions and chronic pain from migraine.
 81. The method ofclaim 79 wherein the pain is caused by a disease or condition selectedfrom the group consisting of osteoarthritis, rheumatoid arthritis,fibromyalgia, migraine, headache, toothache, bum, sunbum, snake bite,spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminalneuralgia, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory boweldisease, irritable bowel syndrome, sinus headache, tension headache,labor, childbirth, menstrual cramps, and cancer.
 82. A method fortreating or preventing a disease or condition selected from the groupconsisting of depression, Parkinson's disease, drug abuse, alcoholabuse, gastritis, urinary incontinence, premature ejaculation, diarrhea,cardiovascular disease, and respiratory diseases, said method comprisingthe step of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate of claim36.
 83. The method of claim 79 wherein said therapeutically effectiveamount comprises a dose range of from about 0.1 mg to about 1,000 mg.84. The method of claim 79 wherein said therapeutically effective amountcomprises a dose range of from about 50 mg to about 1000 mg.
 85. Themethod of claim 79 wherein said therapeutically effective amountcomprises a dose range of from about 100 mg to about 1000 mg.
 86. A kitcomprising in one or more containers an amount of the composition ofclaim 36 effective to treat or prevent mild to severe pain.
 87. Apharmaceutical composition comprising a compound, salt or solvateaccording to claim 37 admixed with a pharmaceutically acceptablecarrier, excipient or diluent.
 88. A veterinary composition comprising acompound, salt or solvate according to claim 37 admixed with aveterinarily acceptable carrier, excipient or diluent.
 89. A method forpreventing or treating mild to severe pain, said method comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate of claim37.
 90. The method of claim 89 wherein the pain is selected from thegroup consisting of inflammatory pain, centrally mediated pain,peripherally mediated pain, visceral pain, structural related pain,cancer pain, soft tissue injury related pain, progressive diseaserelated pain, neuropathic pain and acute pain from acute injury, acutepain from trauma, acute pain from surgery, chronic pain from headache,chronic pain from neuropathic conditions, chronic pain from post-strokeconditions and chronic pain from migraine.
 91. The method of claim 89wherein the pain is caused by a disease or condition selected from thegroup consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia,migraine, headache, toothache, burn, sunbum, snake bite, spider bite,insect sting, neurogenic bladder, benign prostatic hypertrophy,interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causaigia,sciatic neuritis, mandibular joint neuralgia, peripheral neuritis,polyneuritis, stump pain, phantom limb pain, post-operative ileus,cholecystitis, postmastectomy pain syndrome, oral neuropathic pain,Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,meralgia paresthetica, burning-mouth syndrome, post-herpetic neuralgia,trigeminal neuralgia, cluster headache, migraine headache, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,postherpetic neuralgia, trigeminal neuralgia, optic neuritis,postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault'sneuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia,idiopathic neuralgia, intercostals neuralgia, mammary neuralgia,Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, redneuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbitalneuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowelsyndrome, sinus headache, tension headache, labor, childbirth, menstrualcramps, and cancer.
 92. A method for treating or preventing a disease orcondition selected from the group consisting of depression, Parkinson'sdisease, drug abuse, alcohol abuse, gastritis, urinary incontinence,premature ejaculation, diarrhea, cardiovascular disease, and respiratorydiseases, said method comprising the step of administering to a mammalin need of such treatment a therapeutically effective amount of acompound, salt or solvate of claim
 37. 93. The method of claim 89wherein said therapeutically effective amount comprises a dose range offrom about 0.1 mg to about 1,000 mg.
 94. The method of claim 89 whereinsaid therapeutically effective amount comprises a dose range of fromabout 50 mg to about 1000 mg.
 95. The method of claim 89 wherein saidtherapeutically effective amount comprises a dose range of from about100 mg to about 1000 mg.
 96. A kit comprising in one or more containersan amount of the composition of claim 37 effective to treat or preventmild to severe pain.
 97. A pharmaceutical composition comprising acompound, salt or solvate according to claim 38 admixed with apharmaceutically acceptable carrier, excipient or diluent.
 98. Aveterinary composition comprising a compound, salt or solvate accordingto claim 38 admixed with a veterinarily acceptable carrier, excipient ordiluent.
 99. A method for preventing or treating mild to severe pain,said method comprising the step of administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound, salt orsolvate of claim
 38. 100. The method of claim 99 wherein the pain isselected from the group consisting of inflammatory pain, centrallymediated pain, peripherally mediated pain, visceral pain, structuralrelated pain, cancer pain, soft tissue injury related pain, progressivedisease related pain, neuropathic pain and acute pain from acute injury,acute. pain from trauma, acute pain from surgery, chronic pain fromheadache, chronic pain from neuropathic conditions, chronic pain frompost-stroke conditions and chronic pain from migraine.
 101. The methodof claim 99 wherein the pain is caused by a disease or conditionselected from the group consisting of osteoarthritis, rheumatoidarthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn,snake bite, spider bite, insect sting, neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminalneuralgia, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory boweldisease, irritable bowel syndrome, sinus headache, tension headache,labor, childbirth, menstrual cramps, and cancer.
 102. A method fortreating or preventing a disease or condition selected from the groupconsisting of depression, Parkinson's disease, drug abuse, alcoholabuse, gastritis, urinary incontinence, premature ejaculation, diarrhea,cardiovascular disease, and respiratory diseases, said method comprisingthe step of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate of claim38.
 103. The method of claim 99 wherein said therapeutically effectiveamount comprises a dose range of from about 0.1 mg to about 1,000 mg.104. The method of claim 99 wherein said therapeutically effectiveamount comprises a dose range of from about 50 mg to about 1000 mg. 105.The method of claim 99 wherein said therapeutically effective amountcomprises a dose range of from about 100 mg to about 1000 mg.
 106. A kitcomprising in one or more containers an amount of the composition ofclaim 38 effective to treat or prevent mild to severe pain.
 107. Apharmaceutical composition comprising a compound, salt or solvateaccording to claim 39 admixed with a pharmaceutically acceptablecarrier, excipient or diluent.
 108. A veterinary composition comprisinga compound, salt or solvate according to claim 39 admixed with aveterinarily acceptable carrier, excipient or diluent.
 109. A method forpreventing or treating mild to severe pain, said method comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate of claim39.
 110. The method of claim 109 wherein the pain is selected from thegroup consisting of inflammatory pain, centrally mediated pain,peripherally mediated pain, visceral pain, structural related pain,cancer pain, soft tissue injury related pain, progressive diseaserelated pain, neuropathic pain and acute pain from acute injury, acutepain from trauma, acute pain from surgery, chronic pain from headache,chronic pain from neuropathic conditions, chronic pain from post-strokeconditions and chronic pain from migraine.
 111. The method of claim 109wherein the pain is caused by a disease or condition selected from thegroup consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia,migraine, headache, toothache, burn, sunburn, snake bite, spider bite,insect sting, neurogenic bladder, benign prostatic hypertrophy,interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia,sciatic neuritis, mandibular joint neuralgia, peripheral neuritis,polyneuritis, stump pain, phantom limb pain, post-operative ileus,cholecystitis, postmastectomy pain syndrome, oral neuropathic pain,Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,meralgia paresthetica, burning-mouth syndrome, post-herpetic neuralgia,trigeminal neuralgia, cluster headache, migraine headache, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,postherpetic neuralgia, trigeminal neuralgia, optic neuritis,postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault'sneuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia,idiopathic neuralgia, intercostals neuralgia, mammary neuralgia,Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, redneuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbitalneuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowelsyndrome, sinus headache, tension headache, labor, childbirth, menstrualcramps, and cancer.
 112. A method for treating or preventing a diseaseor condition selected from the group consisting of depression,Parkinson's disease, drug abuse, alcohol abuse, gastritis, urinaryincontinence, premature ejaculation, diarrhea, cardiovascular disease,and respiratory diseases, said method comprising the step ofadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound, salt or solvate of claim
 39. 113. Themethod of claim 109 wherein said therapeutically effective amountcomprises a dose range of from about 0.1 mg to about 1,000 mg.
 114. Themethod of claim 109 wherein said therapeutically effective amountcomprises a dose range of from about 50 mg to about 1000 mg.
 115. Themethod of claim 109 wherein said therapeutically effective amountcomprises a dose range of from about 100 mg to about 1000 mg.
 116. A kitcomprising in one or more containers an amount of the composition ofclaim 39 effective to treat or prevent mild to severe pain.
 117. Acompound of Formula (Ib):

wherein: G is bromo, chloro, cyano, trifluoromethanesulfonyloxy,C₁₋₈alkanyloxycarbonyl, carboxy, —C(Z)NR₁R₂, C₆₋₁₀aryl, C₆₋₁₀arylthio,or a heterocycle selected from the group consisting of imidazolyl,triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl,triazinyl, furyl, indazolyl, indolyl, indolinyl, isothiazolyl,isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, and pyridinyl; wherein the C₆₋₁₀aryl group in theC₆₋₁₀aryl-containing substituents of G and the heterocycles of G areoptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, C₂₋₈alkenyl,C₂₋₈alkynyl, C₁₋₈alkanyloxy, hydroxy(C₁₋₈)alkanyl, carboxy(C₁₋₈)alkanyl,C₁₋₈alkanylcarbonylamino, halogen, hydroxy, cyano, nitro, oxo, thioxo,amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₈alkanylthio,C₁₋₈alkanylsulfonyl, C₁₋₈alkanylsulfonylamino, aminocarbonyl,aminothiocarbonyl, am inocarbonylamino, aminothiocarbonylamino,C₁₋₈alkanylaminocarbonyl, di(C₁₋₈alkanyl)aminocarbonyl, andC₁₋₆alkanyloxycarbonylamino; R₁ is a substituent selected from the groupconsisting of hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, and C₂₋₈alkynyl; R₂ isa substituent selected from the group consisting of hydrogen;C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkynyl; C₆₋₁₀aryl; and C₃₋₈cycloalkanyl;provided that when Z is O or S, R₂ is other than hydrogen orunsubstituted C₁₋₈alkanyl; and, wherein C₁₋₈alkanyl of R₂ is optionallysubstituted with one to three substituents independently selected fromthe group consisting of phenyl, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, C₁₋₆alkanyloxy, C₁₋₆alkanylthio, hydroxy, fluoro,chloro, cyano, aminocarbonyl, C₁₋₈alkanylaminocarbonyl,di(C₁₋₈alkanyl)aminocarbonyl, C₁₋₆alkanyloxycarbonyl, and aryloxy;wherein the phenyl and aryloxy substituents of C₁₋₈alkanyl areoptionally further substituted with, and the C₆₋₁₀aryl andC₃₋₈cycloalkanyl substituents of R₂ are optionally substituted with, oneto three substituents independently selected from the group consistingof C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy,trifluoromethyl, trifluoromethoxy, phenyl, halogen, cyano, hydroxy,C₁₋₈alkanylthio, C₁₋₈alkanylsulfonyl, and C₁₋₈alkanylsulfonylamino; orR₁ and R₂ taken together with the nitrogen to which they are attachedform a 5-7 membered cycloheteroalkyl optionally substituted with phenyl(wherein phenyl is optionally substituted with one to three C₁₋₄alkanylor C₁₋₄alkanyloxy substituents) and one to two additional substituentsindependently selected from the group consisting of C₁₋₈alkanyl,hydroxy(C₁₋₈)alkanyl, hydroxy, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, and halogen; or, R₁ and R₂ taken together with thenitrogen to which they are attached form a 5-7 membered cycloheteroalkyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, hydroxy(C₁₋₈)alkanyl,hydroxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, and halogen; R₃is a substituent selected from the group consisting of hydrogen,C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and heteroaryl(C₁₋₈)alkanylwherein the heteroaryl is selected from the group consisting ofbenzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indazolyl,indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; whereinphenyl, naphthyl and heteroaryl are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino,di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen,hydroxy, cyano, fluoro(C₁₋₆)alkanyl, thioureido, andfluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl and heteroaryl areoptionally substituted with alkanyl or alkanyloxy substituents attachedto adjacent carbon atoms, the two substituents can together form a fusedcyclic alkanyl or cycloheteroalkanyl selected from the group consistingof —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and —O(CH₂)₁₋₃O—; R₄ is one tothree substituents independently selected from the group consisting ofhydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl(C₂₋₆)alkynyl,C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl,aminocarbonyl, C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen,hydroxy, mercapto, aminothiocarbonyl, amidino, hydroxyamidino,phenylcarbonyl, —C(═NOH)phenyl, aminomethyl, hydroxymethyl,methanesulfonylamino, C₆₋₁₀arylamino (wherein C₆₋₁₀aryl is optionallysubstituted with one to three substitutents independently selected fromthe group consisting of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy),dihydroimidazolyl, formylamino, thioformylamino, pyridinylamino, cyano,hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl,fluoroalkanyl and fluoroalkanyloxy; or optionally, when R₄ is twosubstituents attached to adjacent carbon atoms, the two substituentstogether form a single fused moiety; wherein the fused moiety isselected from the group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—,—(CH₂)₂₋₄O—, —O(CH₂)₁₋₃O— and —S—C(NH₂)═N—; R₅ is one to twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl,C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl andfluoro(C₁₋₆)alkanyloxy; A is absent or —(CH₂)_(m)—, wherein m is 2 or 3;Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—; X is O or S n is 0 or 1; Z is O, S,NH, N(C₁₋₆alkanyl), N(OH), N(OC₁₋₆alkanyl), or N(phenyl); andenantiomers, diastereomers, tautomers, solvates, or pharmaceuticallyacceptable salts thereof.
 118. The compound according to claim 117wherein G is bromo or cyano.